N6-cyclopentyl-3'-substituted-xylofuranosyladenosines: A new class of non-xanthine adenosine A1 receptor antagonists

Article abstract of DOI:10.1021/jm970176k

The present study explores the C-3' site of the 3-deoxy-3-xylofuranosyl ring of nucleoside analogues with an adenine or N⁶-cyclopentyladenine (CPA) base moiety and evaluates the effect on adenosine receptor affinity. Two series of sugar-modifie

Full text of DOI:10.1021/jm970176k

J . Med. Chem. 1997, 40, 3765-3772
3765
N6-Cyclop en tyl-3′-su bstitu ted -xylofu r a n osyla d en osin es: A New Cla ss of
Non -Xa n th in e Ad en osin e A1 Recep tor An ta gon ists
Serge Van Calenbergh,† J acobien K. von Frijtag Drabbe Ku¨nzel,‡ Norbert M. Blaton,§ Oswald M. Peeters,§
J ef Rozenski,| Arthur Van Aerschot,| Andre De Bruyn,| Denis De Keukeleire,† Adriaan P. IJ zerman,‡ and
Piet Herdewijn*,†,|
Laboratory for Medicinal Chemistry (FFW), University of Ghent, Harelbekestraat 72, B-9000 Gent, Belgium, Leiden/
Amsterdam Center for Drug Research, Division of Medicinal Chemistry, P.O. Box 9502, 2300 RA Leiden, The Netherlands,
Laboratory for Analytical Chemistry and Medicinal Physicochemistry, Faculty of Pharmaceutical Sciences, Catholic University
of Leuven, Belgium, and Laboratory for Medicinal Chemistry, Rega Institute, Catholic University of Leuven, Belgium
Received March 17, 1997X
The present study explores the C-3′ site of the 3-deoxy-3-xylofuranosyl ring of nucleoside
analogues with an adenine or N6-cyclopentyladenine (CPA) base moiety and evaluates the effect
on adenosine receptor affinity. Two series of sugar-modified adenosines, i.e., 3′-amido-3′-
deoxyadenosines and 3′-amidated 3′-deoxyxylofuranosyladenines, were synthesized and tested
for their affinity at A1 and A2a receptors in rat brain cortex and rat striatum, respectively.
The modest affinity found in the “xylo series” prompted us to synthesize the corresponding
N6-cyclopentyl derivatives, which proved to be well accommodated by the A1 receptors with
potencies in the lower nanomolar range. This represents a new perspective in the purinergic
field. The absence of a GTP-induced shift, i.e., the ratio between the affinities measured in
the presence and absence of 1 mM GTP indicates an antagonistic behavior of this new class of
CPA analogues.
In tr od u ction
(CPX) as antagonist for A1)7 and triazoloquinazoline
series (e.g., CGS 15943,8 an antagonist with moderate
selectivity for A2a). 2-Chloro-N6-(3-iodobenzyl)-5′-(me-
thylcarboxamoyl)adenosine (2Cl-IB-MECA) is an ex-
ample of an A3 receptor agonist.9
Although considerable efforts in the area of purinergic
receptor related research have furnished many potent
and selective ligands for adenosine receptors, critics
claim that, with the exception of adenosine itself, none
have been approved as drugs. Nevertheless, the poten-
tial role of adenosine receptors as a target for drug
design was recently demonstrated most elegantly by
Nyce and Metzger.1 They developed a phosphorothioate
21-deoxynucleotide sequence complementary to the m-
RNA that codes for adenosine A1 receptor protein in
rabbit airway smooth muscle tissue in order to block
synthesis of the receptor. Rabbits treated with an
aerosol solution of this antisense DNA developed less
bronchoconstriction when challenged with adenosine or
dust-mite allergen. These findings indicate that the
adenosine A1 receptor is an important mediator of
airway obstruction and inflammation.
Adenosine receptors are subdivided in A1, A2, and the
recently identified A3 receptors,2,3 which have been
cloned from different species.4 The A2 class is further
subdivided in A2a and A2b. The effect of numerous
modifications of the adenosine scaffold on affinity and
intrinsic activity has been investigated. In general,
substitution at the N6 position of the adenine moiety
of adenosine, e.g. N6-cyclohexyladenosine (CHA) and N6-
cyclopentyladenosine (CPA), enhances the affinity for
the A1 receptor.5 Bulky substituents at the 2-position
of the adenine moiety, e.g. CGS 21680A (Figure 1),
increase the A2a receptor selectivity.6 Ligands for the
A1 and A2a receptors have also been found in the
xanthine series (e.g., 1,3-dipropyl-8-cyclopentylxanthine
Except for a certain freedom of substitution at the 5′-
position, e.g. by a 5′-uronamide moiety, A1 and A2
receptors are generally proposed to require an un-
changed ribose moiety for adenosine agonist activity.
The secondary hydroxyl groups of the ribose moiety are
believed to be determinants for the intrinsic activity of
adenosine receptor agonists. Most modifications at the
2′- and 3′- positions of the sugar ring or inversions of
chiral centers at these positions were found to abolish
adenosine receptor binding.10 Removal of the 2′- and
3′-hydroxyl groups of N6-substituted adenosine deriva-
tives was shown to result in partial agonists,11 or, in
the case of the 2′,3′-dideoxy analogue of CHA, antagonist
properties.12 Such changes also affect affinity, whereby
the drop in A1 affinity by deletion of the 2′-hydroxyl
moiety is more pronounced than the decrease caused
by removal of the 3′-group.11 Removal of the 2′-hydroxyl
group of R-PIA (N6-(R)-(1-phenyl-2-propyl)adenosine),
for example, led to an 800-fold decrease in A1 receptor
affinity, while removal of its 3′-hydroxyl group only led
to a 30-fold drop in affinity.10,11 The A1 affinity of 3′-
deoxy-R-PIA is reflected in vivo, where significant
behavioral (CNS) and cardiovascular effects were ob-
served.10 Likewise, 3′-deoxy-CPA exhibits submicro-
molar affinity for the A1 receptor and can thus be
considered as a relatively potent (partial) agonist for this
receptor.11
* To whom correspondence should be addressed.
† Laboratory for Medicinal Chemistry, University of Ghent.
‡ Leiden/Amsterdam Center for Drug Research.
§ Laboratory for Analytical Chemistry and Medicinal Physicochem-
istry, Catholic University of Leuven.
In continuation of our synthetic work on ribose-
modified adenosine analogues,13-15 and in order to
further explore the C-3′ site for modification, we syn-
thesized a series of 3′-amido-3′-deoxyxylofuranosyl ad-
enines (2a -d and 7a -l) together with a number of 3′-
| Laboratory for Medicinal Chemistry, Catholic University of Leu-
ven.
X Abstract published in Advance ACS Abstracts, October 15, 1997.
S0022-2623(97)00176-3 CCC: $14.00 © 1997 American Chemical Society

3766 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23
Van Calenbergh et al.
F igu r e 1. Structures of well-known adenosine receptor ligands and modulators.
Sch em e 1
amido-3′-deoxyadenosines (formulas not shown). These
compounds were tested in vitro for their affinity for the
adenosine A1 and A2a receptors. The affinities found
in the series of the xyloanalogues prompted us to
prepare the compounds in which this favorable 3′-
modification is combined with a N6-cyclopentyl ring.
a suitable carboxylic acid together with N,N ′-dicyclo-
hexylcarbodiimide (DCC) and N-hydroxysuccinimide
(NHS) as coupling agents (Scheme 1). Protection of the
free hydroxyl groups or 6-NH2 did not seem necessary,
since only minor formation of the bis-acylated products
was observed.
N6-Cyclopentyladenosine5 (3) was converted to its 3′-
azidoxylosyl analogue using the method of Moffatt and
co-workers17 as it was modified by Hansske and Rob-
Ch em istr y
Compounds 2a -d were prepared by amidation of
amine 116 with benzoic anhydride in the case of 2a , or

Non-Xanthine Adenosine A1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23 3767
Resu lts a n d Discu ssion
The affinity of the 3′-amido-3′-deoxyadenosines (men-
tioned in ref 15) for these receptors was low: only
marginal (i.e., E10%) displacement of radioligand is
observed at 10 µM concentration (results not shown).
The 3′-amidated 3′-deoxyxylofuranosyl counterparts
(2a -d ) proved to be better tolerated at these receptors
and displayed a Ki of 3-17 µM at A1 and 2-12 µM at
A2a receptors. Here, we demonstrate the possibility to
escape from the necessity of conserving the ribosyl
configuration of adenosine for affinity.
Drastic (18-31-fold) improvement in potency toward
A1 receptors was obtained with the N6-cycopentyl con-
geners, i.e. 7a ,k ,l, suggesting the compatibility of our
carbohydrate modification with this typical N6-substitu-
ent. A series of structural analogues of the benzamido
derivative (7a ) provides a number of insights into
structure-activity relationships with regard to adeno-
sine receptor binding. Varying substituents in para
position of the benzamido moiety shows the following
trend on A1 receptor affinity: NO2 < H < OMe < Cl E
Me. Adding a further chloro or methyl group in meta
on the aromatic ring of 7b and 7d , respectively, to give
7g and 7f, further increases activity. Optimization of
the spacer between the phenyl ring and the amido
functionality reveals a length of three methylenes to be
the most favorable. The 3′-azido intermediate 5 dis-
plays a relatively poor affinity for A1 receptors, sug-
gesting the importance of the amide moiety for effective
binding at these receptors. For all analogues synthe-
sized, the GTP shift for the A1 receptor is nearly 1. The
absence of a GTP-induced shift in binding vs radiola-
beled DPCPX (1,3-dipropyl-8-cyclopentylxanthine) an-
tagonist strongly suggests the 3′-amido xylosyl CPA
analogues to be full antagonists for the A1 receptor. This
fact proves that by suitable sugar modification it is
possible to turn a full (CPA) or partial agonist (3′-deoxy-
CPA) into an antagonist. As expected, the effect of the
N6-cyclopentyl substituent is negligible at the A2a recep-
tors (for those compounds for which comparable data
are available). With the exception of compound 5, the
selectivity for A1 vs A2a receptors was thus significantly
improved (e.g., 7f, the most potent A1 ligand of this
series was found to be 160 times selective vs A2a).
The crystal structure of compound 7a reveals the
orientation of the ribose group relative to the adenine
ring system. The compound appears to be in the so-
called syn conformation stabilized by a hydrogen bond
formed between N3 and the 5′-OH group (distance
N3‚‚‚H, 2.0 Å; angle N3‚‚‚H-O, 176°). Generally it is
assumed that the anti conformation (where the ribose
group is turned away from the adenine ring) is essential
for agonistic activity.20 Although certainly not conclu-
sive the syn/anti aspect may explain the antagonistic
properties of this new series of compounds. Other
studies have systematically addressed N9-substitution
other than ribose.10,21,22 Taylor et al. synthesized ribose-
modified analogues of adenosine.10 Of relevance to the
present study were compounds that did not display
agonistic activity in vivo, but retained some affinity
toward adenosine receptors as determined in radioli-
gand binding studies. A 9-(2-tetrahydrofuranyl) sub-
stituent proved acceptable with modest adenosine A1
receptor affinity (Ki value for N6-(2-phenylethyl)-9-(2-
tetrahydrofuran)adenine of 1.5 µM). Olsson and co-
F igu r e 2. ORTEP view of compound 7b as determined by
X-ray crystallography.
ins.18 Thus, 3 was first converted to its 2′,3′-anhydro
analogue 4 by reaction with R-acetoxyisobutyryl bromide
in “moist acetonitrile” followed by alkaline treatment.
Epoxide opening of 4 with NaN3 in hot DMF proceeded
stereo- and regioselectively at the 3′-position to give the
3′-azido nucleoside 5 in good yield. Subsequent reduc-
tion of 5 to 6 proceeded smoothly by catalytic hydroge-
nation. Finally, amidation of 6 with suitable carboxylic
acids yielded the desired 7a -l. Hereto, the use of N,N′-
diisopropylcarbodiimide (DIC) and 1-hydroxybenzotri-
azole hydrate (HOBT) instead of the DCC-NHS com-
bination was found more convenient with respect to
workup and yield.
Str u ctu r a l P r oof of Com p ou n d 7a by X-r a y
An a lysis
The N-glycosidic torsion angle ø has a value of 53.8-
(3)° in the syn range. The syn conformation is stabilized
by the intramolecular H-bond C(5′)-OH‚‚‚N(3). The
2
sugar pucker is E with P ) 165.3(3)° and νmax ) 38.0-
(2)°. The conformation about the exocyclic C-4′-C-5′
bond is +sc with γ ) 45.7(4)°. The N-cyclopentyl ring
adopts the envelope conformation. All oxygen and most
of the nitrogen atoms are involved in a network of
hydrogen bonds. An ORTEP view of the molecule with
the atomic numbering scheme is shown in Figure 2.
Biologica l Eva lu a tion
All modified adenosine and CPA analogues were
tested in radioligand binding assays to determine their
affinities toward adenosine A1 and A2a receptors in rat
brain cortex and rat striatum, respectively (Table 1).
Affinities of the parent 3′-deoxyadenosine and 3′-deoxy-
CPA are included for reasons of comparison. The
compounds were assayed for A1 affinity using the
tritiated antagonist [3H]-1,3-dipropyl-8-cyclopentylxan-
thine (DPCPX). Displacement experiments were per-
formed in the absence and presence of 1 mM GTP,
allowing the determination of the GTP shift (i.e., the
ratio of the apparent Ki values in the presence and
absence of GTP, respectively). This shift is an in vitro
parameter often indicative for intrinsic activity.19 Since
no radiolabeled antagonist is available for A2a receptors,
the tritiated agonist [3H]CGS21680 was used. This
prohibited the determination of a GTP shift on A2a
receptors, and all experiments on these receptors were
done in the absence of GTP. Compounds 1 and 6 do
not display affinity for adenosine receptors, probably
because of protonation of the amino group.

3768 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23
Van Calenbergh et al.
Ta ble 1. Affinities [Ki Values (Standard Errors of the Mean) in the Presence and Absence of GTP] and GTP Shifts of the
(N6-Substituted) 3′-Deoxyadenosine Analogues
Ki (µM)
Ki (µM)
A2a
compd
R6
R3′
A1 - GTP
A1 + GTP
GTP shift
a
H
H
H
H
H
H
7.12 ( 3.62
10.9 ( 2.8
15.2 ( 2.0
2.1 ( 1.4
-
2a
2b
2c
2d
NHCO-Ph
11.1 ( 0.4
1.1 ( 0.3
2.47 ( 0.52
11.8 ( 3.0
1.77 ( 0.48
4.66 ( 1.35
18.6 ( 6.8
2.41 ( 0.52
2.76 ( 1.19
0.58 ( 0.13
0.77-2.45
0.79-2.52
6.85 ( 2.39
3.68 ( 1.50
2.02 ( 0.98
(50%)b
NHCO-(CH2)2O-Ph
NHCO-(CH2)3C6H11
NHCO-(CH2)4-Ph
H
16.9 ( 1.6
12.6 ( 2.0
0.74 ( 0.05
0.75 ( 0.03
0.73 ( 0.04
4.3 ( 1.2
3.59 ( 0.10
7.84 ( 0.37
0.11 ( 0.03
8.47 ( 3.48
0.40 ( 0.13
0.11 ( 0.09
0.20 ( 0.13
0.083 ( 0.015
0.82 ( 0.31
0.0236 ( 0.0025
0.0325 ( 0.0031
0.85 ( 0.29
0.37 ( 0.12
0.13 ( 0.08
0.24 ( 0.03
0.19 ( 0.11
2.68 ( 0.04
5.74 ( 0.58
0.47 ( 0.04
11.2 ( 1.5
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
5
N3
1.4 ( 0.3
7a
7b
7c
7d
7e
7f
7g
7h
7i
NHCO-Ph
0.31 ( 0.05
0.081 ( 0.033
0.13 ( 0.02
0.068 ( 0.010
0.74 ( 0.22
0.0174 ( 0.0042
0.0237 ( 0.0014
0.77 ( 0.24
0.35 ( 0.12
0.10 ( 0.02
0.20 ( 0.03
0.15 ( 0.09
0.80 ( 0.13
0.87 ( 0.29
0.77 ( 0.30
0.84 ( 0.19
0.91 ( 0.08
0.73 ( 0.11
0.73 ( 0.09
0.95 ( 0.31
0.99 ( 0.36
0.94 ( 0.38
0.83 ( 0.16
0.80 ( 0.03
NHCO-Ph-pCl
NHCO-Ph-pOMe
NHCO-Ph-pMe
NHCO-Ph-pNO2
NHCO-Ph-3,4-diMe
NH-CO-Ph-3,4-diCl
NHCO-CH2-Ph
NHCO-(CH2)2-Ph
NHCO-(CH2)3-Ph
NHCO-(CH2)4-Ph
NHCO-(CH2)3-C6H11
7.94 ( 4.48
0.65 ( 0.16
4.23 ( 0.94
(74%)b
7j
7k
7l
a
-, not determined because the addition of deoxycoformycin, necessary to prevent degradation of this compound by adenosine deaminase,
b
disturbed the binding assay. This was not the case for the A1 receptor assay. Percentage radioligand bound to the receptor in the presence
of 10-5 M ligand.
workers explored methyl, ethyl, 2-hydroxyethyl, cyclo-
pentyl, phenyl, and 2-tetrahydrofuranyl substituents at
N-9.21 In this study N6-cyclopentyl-9-ethyladenine was
most potent with a Ki value of 440 nM. More recently,
J acobson and colleagues investigated the relationship
between adenosine A3 receptor affinity and N9-substitu-
tion.22 For comparison adenosine A1 receptor affinities
were also included in this study, showing that again a
2-tetrahydrofuran substituent yielded moderate affinity
for this receptor subtype. From the present study we
conclude that N6-cyclopentylxylofuranosyladenines bear-
ing a substituent of considerably larger size at the 3′-
position can be accommodated as well, and may even
lead to derivatives with enhanced potencies in the lower
nanomolar range.
Exp er im en ta l Section
(1) Ra d ioliga n d Bin d in g Stu d ies. Adenosine A1 receptor
affinities were determined on rat cortical membranes with
[3H]-1,3-dipropyl-8-cyclopentylxanthine (DPCPX) as radioli-
gand according to a protocol published previously.23 Measure-
ments with [3H]DPCPX were performed in the presence and
absence of 1 mM GTP.
Adenosine A2a receptor affinities were determined on rat
striatal membranes with [3H]CGS 21680 as radioligand ac-
cording to J arvis et al.24 All data reflect three or four
independent experiments, performed in duplicate. Data analy-
sis (Ki values) was done with the software program PRISM
(GraphPad, San Diego, CA).
(2) Str u ctu r e Deter m in a tion of 7a by X-r a y Cr ysta l-
logr a p h y.
C
22H26N6O4‚1/2H2O, Mr ) 447.50, orthorhombic,
P212121; a ) 6.6666(5) Å, b ) 15.2695(5) Å, c ) 21.9515(8) Å,
V ) 2234.6(2) Å,3 Z ) 4, Dc ) 1.330 mg m-3; graphite
monochromated Cu KR radiation, λ ) 1.541 78 Å; 2000
observed reflections [I > 2σ(I)], 2209 independent reflections
[R(int) ) 0.0128]; µ ) 0.788 mm-1, F(000) ) 948, T ) 293(2)
Con clu sion
Full adenosine A1 receptor agonists such as CPA and
other N6-substituted adenosine analogues have previ-
ously been shown to become partial agonists upon
deletion of the 3-hydroxyl moiety. The present study
further explored the C-3′ site for modification. The most
interesting and unexpected finding was that the 3′-
amidated xylofuranosyl analogues of CPA displayed
potent affinities for the A1 adenosine receptor. The so-
called GTP shifts indicate these analogues to be full
antagonists for this receptor type. These findings
represent a new perspective in the purinergic field and
may provide new non-xanthine leads with improved
antagonist activity for use as cardiotonics, cognition
enhancers, or antiasthmatics. Determination of in vivo
activity of most potent congeners is in progress.
K, final R ) 0.0335[I > 2σ(I)], ∆Fmax ) 0.124 e Å-3, ∆Fmin
)
-0.136 e Å-3; structure solution using SIR92,25 structure
refinement using SHELXL93.26
(3) Syn th esis. Gen er a l. Melting points were determined
in capillary tubes with an Electrothermal (IA 9000 series)
digital melting point apparatus and are uncorrected. For
compounds 2b, 2d , 6, 7f, and 7g, determination of melting
points was impossible since decomposition occurred prior to
melting. Ultraviolet spectra were recorded in MeOH with a
Schimadzu 2100 UV/vis spectrophotometer. 1H NMR spectra
at 19° were obtained with a Bruker WH 360 spectrometer. The
solvent signal of DMSO-d6 (2.50 ppm) was used as secondary
reference. All signals assigned to amino and hydroxyl groups
were exchangeable with D2O. 13C NMR spectra were mea-
sured on a Varian Gemini 200 MHz spectrometer with the
solvent signal of DMSO-d6 (39.70 ppm) as secondary reference.

Non-Xanthine Adenosine A1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23 3769
Liquid secondary-ion mass spectra (LSIMS) were obtained
using a Kratos concept H mass spectrometer (Kratos, Manches-
ter, UK).
36.81 ((CH2)3-C6H11), 55.91 (C-3′), 60.44 (C-5′), 76.91 (C-2′),
79.89 (C-4′), 89.27 (C-1′), 119.5 (C-5), 140.74 (C-8), 148.49 (C-
4), 152.28 (C-2), 156.28 (C-6), 172.91 (CO); MS (LSIMS,
thioglycerol) m/z 419 (M + H)+, 284 (M - B)+, 136 (B + 2H)+.
Anal. (C20H30N6O4‚C2H5OH) C, H, N.
1
Elemental analyses were performed at the university of
Konstanz, Germany, and are within (0.4% of theoretical
values unless otherwise specified.
Precoated Merck silica gel F254 plates were used for TLC,
and spots were examined with UV light at 254 nm and sulfuric
acid-anisaldehyde spray. Column chromatography was per-
formed on SU¨ D-Chemie silica gel (0.2-0.05 mm).
Anhydrous solvents were obtained as follows: pyridine was
refluxed overnight in the presence of KOH and distilled; CH2-
Cl2 was obtained by distillation after reflux overnight with
CaH2; MeOH was obtained by distillation after refluxing
overnight on CaH2; water was removed from absolute DMF
by storing on Linde type 4 Å molecular sieves, followed by
distillation under reduced pressure.
9-[3-Deoxy-3-(5-p h en ylva ler a m id o)-â-D-xylofu r a n osyl]-
a d en in e (2d ). This compound was prepared as described for
2b, using 425 mg (1.6 mmol) of the amine 1, 285 mg (1.6 mmol)
of 5-phenylvaleric acid, 184 mg (1.6 mmol) of NHS, and 330
mg (1.6 mmol) of DCC. The title compound was obtained as
a white solid: 210 mg (32% yield); 1H NMR (DMSO-d6) δ 1.57
(m, 4 H), 2.25 (m, 2 H), 2.58 (m, 2 H) (4 CH2 of valeramide),
3.45 (m, dd after D2O exchange, J 5B′,4′ ) 4.5 Hz, J 5B′,5A′ ) -12.4
Hz, H-5B′), 3.56 (m, dd after D2O exchange, J 5A′, ) 3.2 Hz,
4′
H-5A′), 4.20 (m, H-4′), 4.41 (app q, t after D2O exchange, J )
6.4 Hz, H-3′), 4.63 (app q, t after D2O exchange, J ) 5.7 Hz,
H-2′), 5.37 (dd, J ) 5.4, 7.2 Hz, 5′-OH), 5.78 (d, H-1′, J ) 5.4
Hz), 5.88 (d, 2′-OH, J ) 5.1 Hz), 7.16 (t, arom H-4), 7.18 (d,
arom H-2,6), 7.26 (t, arom H-3,5), 7.47 (br s, NH2), 8.17 (s,
H-2), 8.35 (s, H-8), 8.63 (d, J ) 8.0 Hz, 3′-NH); 13C NMR
(DMSO-d6) δ 25.52, 31.06, 35.38, 35.76 (4 CH2 of valeramide),
56.29 (C-3′), 60.95 (C-5′), 77.18 (C-2′), 80.21 (C-4′), 89.55 (C-
1′), 119.92 (C-5), 126.26 (Cp), 128.84 (2 Co, 2 Cm), 141.23 (C-8),
142.61 (Cipso), 148.99 (C-4), 152.80 (C-2), 156.58 (C-6), 173.54
(CO); MS (LSIMS, thioglycerol) m/z 449 (M + Na)+, 427 (M +
H)+, 178 (s1), 164 (s2), 136 (B + 2H)+. Anal. (C21H26N6O4‚C2H5-
OH) C, H, N.
9-(3-Ben zam ido-3-deoxy-â-D-xylofu r an osyl)aden in e (2a).
To a cooled (0 °C) suspension of 420 mg (1.58 mmol) of amine
116,27 in 30 mL of dry CH2Cl2-pyridine (3:1) was added 433
mg (1.91 mmol) of benzoic anhydride. After the mixture was
stirred for 3 h at room temperature, the reaction was quenched
with 5 mL of H2O. The mixture was evaporated to dryness
and purified by column chromatography (EtOAc-MeOH, 98:2
and then 95:5) to obtain 287 mg (49%) of the title compound
1
as a white solid: mp 236 °C; H NMR (DMSO-d6) δ 3.54 (m,
H-5B′), 3.67 (m, J 5A′,5B′ ) -12.2 Hz, H-5A′), 4.32 (app q, H-4′),
4.63 (app q, H-3′), 4.78 (app q, J 2′,3′ ) 4.7 Hz, H-2′), 5.27 (t, J
) 5.9 Hz, 5′-OH), 5.86 (d, J ) 4.0 Hz, 2′-OH), 6.00 (d, J ) 4.9
Hz, H-1′), 7.48 (br s, NH2), 7.54 (t, arom H-3,5), 7.59 (t, arom
H-4), 7.87 (d, arom H-2,6), 8.07 (s, H-2), 8.40 (s, H-8), 9.34 (d,
J ) 8.1 Hz, 3′-NH); 13C NMR (DMSO-d6) δ 57.28 (C-3′), 60.48
(C-5′), 77.82 (C-2′), 80.42 (C-4′), 89.93 (C-1′), 119.75 (C-5),
127.27, 128.67 (2 Co, 2 Cm), 131.65 (Cp), 134.55 (Cipso), 140.84
(C-8), 148.47 (C-4), 152.34 (C-2), 156.47 (C-6), 166.94 (CO); MS
(LSIMS, thioglycerol) m/z 393 (M + Na)+, 371 (M + H)+, 178
(s1),28 164 (s2), 136 (B + 2H)+, 105 (C6H5CO)+. Anal.
(C17H18N6O4‚C2H5OH) C, H, N.
9-(2,3-An h yd r o-â-D-r ibofu r a n osyl)-N6-cyclop en tyla d e-
n in e (4). To a suspension of 5.71 g (17.03 mmol) of N6-
cyclopentyladenosine (3) in 150 mL of dry acetonitrile, con-
taining 15 mL of CH3CN-H2O (100:1), was added 9.9 mL (68
mmol) of R-acetoxyisobutyryl bromide, and the mixture was
stirred at room temperature for 3 h. The clear solution was
diluted with 150 mL of saturated aqueous NaHCO3 solution
and extracted twice with 200 mL of EtOAc. The combined
organic layers were washed with water, dried (MgSO4), and
evaporated. The residue was dissolved in 0.4 N methanolic
sodium methoxide and kept overnight at room temperature.
It was then neutralized with acetic acid-water (1:9) and
evaporated on Celite. Purification by column chromatography
yielded 3.82 g (71% yield) of 4 as a white foam: 1H NMR
(DMSO-d6) δ 1.55 (br s, 4H), 1.70 (br s, 2H), 1.90 (br s, 2H)
(cyclopentyl), 3.54 (m, H-5′), 4.17 (app t, J 4′-5A′,5B′ ) 5.2 Hz,
H-4′), 4.22 (d, J 3′,2′ ) 2.6, H-3′), 4.44 (d, H-2′), 4.52 (br s,
cyclopentyl CHNH), 5.05 (t, J ) 5.1 Hz, 5′-OH), 6.20 (s, H-1′),
7.75 (br d, J ) 7 Hz, NH), 8.22 (br s, H-2), 8.33 (s, H-8); MS
(LSIMS, thioglycerol) m/z 340 (M + Na)+, 318 (M + H)+, 249
(M + H - cyclopentyl), 232 (s2), 204 (B + 2H)+, 136 (B -
cyclopentyl + 2H)+.
9-[3-Deoxy-3-(3-p h en oxyp r op ion a m id o)-â-D-xylofu r a -
n osyl]a d en in e (2b). To a cooled (-20 °C), stirred suspension
of 565 mg (2.13 mmol) of 1 and 353 mg (2.13 mmol), of
3-phenoxypropionic acid in 20 mL of dry DMF were added
NHS (245 mg, 2.13 mmol) and DCC (439 mg, 2.13 mmol) and
stirring was continued for 24 h at room temperature. The
reaction mixture was filtered and the filtrate evaporated. The
obtained residue was purified by column chromatography
(CH2Cl2, then CH2Cl2-MeOH, 95:5 and finally 90:10) to yield
a white solid, which after crystallization from EtOH gave 280
mg (32%) of the pure title compound: 1H NMR (DMSO-d6) δ
2.68 (m, COCH2), 3.54 (m, 2 dd after D2O exchange, H-5′),
4.17-4.26 (m, 3 H, H-4′, Ph-OCH2), 4.45 (app q, t after D2O
exchange, J ) 5.9 Hz, H-2′, coupling constant measured after
D2O exhange), 4.68 (app q, t after D2O exchange, J ) 6.5 Hz,
H-3′), 5.43 (dd, J ) 4.4, 7.5 Hz, 5′-OH), 5.78 (d, J ) 5.6 Hz,
H-1′), 5.90 (d, J ) 5.4 Hz, 2′-OH), 6.90 (m, arom H-2,4,6), 7.27
(t, arom H-3,5), 7.47 (br s, NH2), 8.15 (s, H-2), 8.33 (s, H-8),
8.82 (d, 3′-NH, J ) 8.0 Hz); 13C NMR (DMSO-d6) δ 36.03 (CH2-
CO), 56.36 (C-3′), 60.89 (C-5′), 64.42 (Ph-O-CH2), 76.95 (C-2′),
80.17 (C-4′), 89.46 (C-1′), 114.87 (2 Co), 121.19 (Cp), 130.06 (2
Cm), 141.22 (C-8), 148.98 (C-4), 152.73 (C-2), 156.53 (C-6),
158.79 (Cipso), 171.07 (CO); MS (LSIMS, thioglycerol) m/z 415
(M + H)+, 149 (PhO(CH2)2CO)+, 136 (B + 2H)+. Anal.
(C19H22N6O5‚C2H5OH) C, H, N.
9-(3-Azid o-3-d e oxy-â-D-xylofu r a n osyl)-N 6-cyclop e n -
tyla d en in e (5). A mixture of 3.82 g of the epoxide 4 and 3.91
g (60 mmol) of NaN3 in 60 mL of DMF was stirred for 3 days
at 80 °C. The solvent was evaporated; the residue was
adsorbed on Celite and purified by column chromatography
(EtOAc, then EtOAc-MeOH, 95:5 and finally 90:10), yielding
1
2.42 g (42%) of 5 as a white solid: mp 113 °C dec; H NMR
(DMSO-d6) δ 1.50 (br s, 4H), 1.70 (br s, 2H), 1.93 (br s, 2H)
(cyclopentyl), 3.60-3.74 (m, H-5′), 4.28-4.39 (m, 2H, H-3′,4′),
4.52 (br s, cyclopentyl CH-NH), 4.80 (app q, J 2′,3′ ) 5.4 Hz,
H-2′), 5.41 (t, J ) 5.6 Hz, 5′-OH), 5.84 (d, J ) 5.3 Hz, H-1′),
6.20 (d, J ) 5.2 Hz, 2′-OH), 7.80 (d, NH), 8.20 (br s, H-2), 8.30
(s, H-8); MS (LSIMS, thioglycerol) m/z 361 (M + H)+, 318 (M
- N3)+, 246 (s1), 232 (s2), 204 (B + 2H)+, 136 (B - cyclopentyl
+ 2H)+. Anal. (C15H20N8O3) C, H; N: calcd, 31.10; found,
28.85.
9-[3-Deoxy-3-(4-cycloh exylb u t yr a m id o)-â-D-xylofu r a -
n osyl]a d en in e (2c). This compound was prepared as de-
scribed for 2b, using 425 mg (1.6 mmol) of the amine 1, 272
mg (1.6 mmol) of 4-cyclohexanebutyric acid, 184 mg (1.6 mmol)
of NHS, and 330 mg (1.6 mmol) of DCC. The title compound
was obtained as a white solid: 265 mg (40% yield); mp 107 °C
9-(3-Am in o-3-d eoxy-â-D-xylofu r a n osyl)-N6-cyclop en -
tyla d en in e (6). A solution of 2.42 g (6.7 mmol) of 5 in 30 mL
of MeOH was hydrogenated at room temperature and 1100
psi of pressure in the presence of 10% Pd/C (0.5 g). The
mixture was filtered over a Celite pad and evaporated to yield
2.21 g (95%) of 6 as a white solid, which was sufficiently pure
for the next step: 1H NMR (DMSO-d6) δ 1.5-2.0 (m, 8H,
cyclopentyl), 3.54 (app t, J ) 6.3 Hz, H-2′), 3.70 (m, H-3′,
H-5A′), 4.19 (app dt, H-4′), 4.50 (br s, cyclopentyl CH-NH), 5.0
(br s, 3H, 5′-OH, 3′-NH2), 5.78 (d, J ) 5.2 Hz, H-1′), 5.90 (br s,
2′-OH), 7.66 (br d, J ) 6 Hz, NH-cyclopentyl), 8.20 (br s, H-2),
1
dec; H NMR (DMSO-d6) δ 0.80 (dd, 2H), 1.13 (m, 6H), 1.5-
1.7 (m, 7H), 2.17 (m, 2H) ((CH2)3C6H11)), 3.50 (m, H-5′), 4.20
(m, H-4′), 4.39 (app q, t after D2O exchange, J ) 5.9 Hz, H-3′),
4.60 (app q, t after D2O exchange, J ) 5.3 Hz, H-2′), 5.32 (app
t, 5′-OH), 5.77 (d, J ) 5.3 Hz, H-1′), 5.88 (d, 2′-OH), 7.45 (br s,
NH2), 8.17 (s, H-2), 8.34 (s, H-8), 8.62 (d, J ) 8.4 Hz, 3′-NH);
13C NMR (DMSO-d6) δ 22.81, 25.88, 26.26, 32.88, 35.78, 36.46,

3770 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23
Van Calenbergh et al.
8.39 (s, H-8); MS (FAB, thioglycerol) m/z 336 (M + 2H)+, 204
(B + 2H)+, 136 (B - cyclopentyl + 2H)+.
246 (s1), 232 (s2), 204 (B + 2H)+, 139 (COC6H4-p-Cl)+, 136 (B
- cyclopentyl + 2H)+. Anal. (C22H25N6O4Cl) C, H, N.
9-[3-Deoxy-3-(4-m eth oxyben zam ido)-â-D-xylofu r an osyl]-
N6-cyclop en tyla d en in e (7c): mp 240-241.5 °C; 1H NMR
(DMSO-d6) δ 1.5-1.8 (m, 6H), 1.92 (br s, 2H) (cyclopentyl),
3.52 (m, H-5B′), 3.66 (m, H-5A′), 3.82 (s, OCH3), 4.30 (app q,
H-4′), 4.52 (br s, cyclopentyl CH-NH), 4.60 (app q, H-3′), 4.78
(app q, H-2′), 5.25 (br s, 5′-OH), 5.85 (d, J ) 4.5 Hz, H-1′),
5.99 (d, J ) 4.9 Hz, 2′-OH), 7.10 (d, arom H-3,5), 7.87 (d, arom
H-2,6), 7.90 (br s, NH-cyclopentyl), 8.20 (br s, H-2), 8.40 (s,
H-8), 9.19 (d, NHCO); 13C NMR (DMSO-d6) δ 23.67, 32.22,
51.82 (cyclopentyl), 55.63 (OCH3), 57.37 (C-3′), 60.54 (C-5′),
78.01 (C-2′), 80.57 (C-4′), 90.15 (C-1′), 114.00 (2 Cm), 120.82
(C-5), 126.66 (Cipso), 129.18 (2 Co), 140.65 (C-8), 147.8 (C-4),
152.40 (C-2), 154.73 (C-6), 162.04 (Cp), 166.44 (CO); MS
(LSIMS, thioglycerol) m/z 491 (M + Na)+, 469 (M + H)+, 266
(M - B), 246 (s1), 232 (s2), 204 (B + 2H)+, 136 (B - cyclopentyl
+ 2H)+, 135 (COC6H5-p-OMe)+. Anal. (C23H28N6O5) C, H, N.
9-[3-Deoxy-3-(4-m eth ylben za m id o)-â-D-xylofu r a n osyl]-
N6-cyclop en tyla d en in e (7d ): mp 239.5-241 °C; 1H NMR
(DMSO-d6) δ 1.5-1.75 (m, 6H), 1.93 (br s, 2H) (cyclopentyl),
2.40 (s, CH3), 3.51 (m, H-5B′), 3.66 (m, H-5A′), 4.30 (app q,
H-4′), 4.51 (br s, cyclopentyl CH-NH), 4.60 (app q, H-3′), 4.75
(app q, H-2′), 5.25 (br s, 5′-OH), 5.85 (d, J ) 4.5 Hz, H-1′),
6.00 (d, J ) 4.9 Hz, 2′-OH), 7.38 (d, arom H-3,5), 7.79 (d, arom
H-2,6), 7.93 (br s, NH-cyclopentyl), 8.17 (br s, H-2), 8.40 (s,
H-8), 9.35 (br s, NH-CO); 13C NMR (DMSO-d6) δ 21.19 (CH3),
23.67, 32.18, 51.72 (cyclopentyl), 57.37 (C-3′), 60.54 (C-5′),
78.07 (C-2′), 80.59 (C-4′), 90.19 (C-1′), 127.36 (2 Co), 129.29 (2
Cm), 131.81 (Cipso), 140.63 (C-8), 141.70 (Cp), 152.34 (C-2),
154.71 (C-6), 166.86 (CO); MS (LSIMS, thioglycerol) m/z 475
(M + Na)+, 453 (M + H)+, 246 (s1), 232 (s2), 204 (B + 2H)+,
136 (B - cyclopentyl + 2H)+, 119 (COC6H4-p-Me)+. Anal.
(C23H28N6O4) C, H, N.
9-(3-Ben za m id o-3-d eoxy-â-D-xylofu r a n osyl)-N6-cyclo-
p en tyla d en in e (7a ). To a solution of 600 mg (1.72 mmol) of
6 in 60 mL of dry CH2Cl2-pyridine (5:1) cooled at 0 °C was
added 428 mg (1.89 mmol) of benzoic anhydride. After the
mixture was stirred for 3 h at room temperature, the reaction
was quenched with 5 mL of H2O. The mixture was evaporated
to dryness and the residue purified by column chromatography
(CH2Cl2, then CH2Cl2-MeOH, 95:5 and finally 90:10) to obtain
the crude title compound. Crystallization from acetone and
petroleum ether gave 500 mg (65%) of pure 7a : mp 161 °C;
1H NMR (DMSO-d6) δ 1.5-1.8 (m, 6H), 1.92 (br s, 2H,
cyclopentyl), 3.55 (m, H-5B′), 3.67 (app dt, J 5A′,5B′ ) -12.3 Hz,
H-5A′), 4.32 (m, H-4′), 4.52 (br s, cyclopentyl CH-NH), 4.62
(m, H-3′), 4.77 (m, H-2′), 5.27 (br s, 5′-OH), 5.86 (d, J ) 4.3
Hz, H-1′), 6.00 (d, J ) 4.8 Hz, 2′-OH), 7.60 (m, arom H-3,4,5),
7.85 (d, arom H-2,6), 7.91 (br s, NH-cyclopentyl), 8.12 (br s,
H-2), 8.39 (s, H-8), 9.39 (d, 3′-NH, J ) 6.7 Hz); 13C NMR
(DMSO-d6) δ 23.60, 32.13, 51.6 (cyclopentyl), 57.32 (C-3′), 60.48
(C-5′), 77.95 (C-2′), 80.49 (C-4′), 90.07 (C-1′), 120.1 (C-5),
127.28, 128.70 (2 Co, 2 Cm), 131.66 (Cp), 134.58 (Cipso), 140.54
(C-8), 147.5 (C-4), 152.25 (C-2), 154.64 (C-6), 166.92 (CO); MS
(LSIMS, thioglycerol) m/z 461 (M + Na)+, 439 (M + H)+, 246
(s1), 232 (s2), 204 (B + 2H)+, 136 (B - cyclopentyl + 2H)+, 105
(PhCO)+. Anal. (C22H26N6O4‚1/2H2O) C, H, N.
9-[3-Deoxy-3-(5-p h en ylva ler a m id o)-â-D-xylofu r a n osyl]-
N6-cyclop en tyla d en in e (7k ). To a cooled (-20 °C) suspen-
sion of 606 mg (1.74 mmol) of 6 and 306 mg (1.72 mmol) of
5-phenylvaleric acid in 40 mL of dry DMF were added 532 mg
(2.58 mmol) of DCC and 296 mg (2.58 mmol) of NHS. The
mixture was allowed to come to room temperature and stirred
for 24 h, after which it was filtered. The filtrate was
evaporated and the residue purified by column chromatogra-
phy (CH2Cl2, then CH2Cl2-MeOH, 95:5 and finally 90:10) to
obtain 370 mg (42%) of 7i as a white solid: mp 81 °C; 1H NMR
(DMSO-d6) δ 1.5-2.6 (m, 16H, cyclopentyl, 4 CH2 of valera-
mide), 3.42 (dd after D2O exchange, J 5B′,4′ ) 4.6 Hz, H-5B′),
3.56 (dd after D2O exchange, J 5A′,4′ ) 3.0 Hz, J 5A′,5B′ ) -12.5
Hz, H-5A′), 4.20 (app q, H-4′), 4.39 (app q, t after D2O
exchange, J ) 6.4 Hz, H-3′), 4.48 (cyclopentyl CH-NH), 4.60
(app q, t after D2O exchange, J ) 5.7 Hz, H-2′), 5.42 (dd, 5′-
OH), 5.76 (d, J ) 5.4 Hz, H-1′), 5.88 (d, 2′-OH), 7.18 (m, 3H,
arom H-2,4,6), 7.28 (t, 2H, arom H-3,5), 7.9 (d, NH-cyclopentyl),
8.24 (br s, H-8), 8.35 (s, H-2), 8.62 (d, NH-CO); 13C NMR
(DMSO-d6) δ 23.98, 32.55, 52.09 (cyclopentyl), 25.51, 31.03,
35.36, 35.76 (4 CH2 of valeramide), 56.29 (C-3′), 60.92 (C-5′),
77.20 (C-2′), 80.21 (C-4′), 89.61 (C-1′), 120.19 (C-5), 126.23 (Cp),
128.82 (2 Co, 2 Cm), 140.81 (C-8), 142.59 (Cipso), 148.2 (C-4),
152.73 (C-2), 154.88 (C-6), 173.47 (CO); MS (LSIMS, thioglyc-
erol) m/z 495 (M + H)+, 246 (s1), 232 (s2), 204 (B + 2H)+, 136
(B - cyclopentyl + 2H)+. Anal. (C26H34N6O4) H, N; C: calcd,
63.12; found, 62.52.
Gen er a l P r oced u r e for th e Syn th esis of th e Rem a in -
in g Der iva tives 7. An amount of 200 mg (0.6 mmol) of 6, 90
mg (0.67 mmol) of HOBT, and 0.6 mmol of the respective
carboxylic acid were dissolved in 10 mL of CH2Cl2. The
mixture was cooled at 0 °C, and 100 µL (0.64 mmol) of DIC
was added. After the mixture was stirred for 2 h, it was
evaporated, and the residue purified on silica gel eluted with
CH2Cl2-MeOH (98:2 and then 95:5). The desired compounds
were obtained as amorphous white powders in 75-90% yield.
Analytical samples were obtained after crystallization from
MeOH (7b-g) or a second purification on silica gel (7h -k ).
9-[3-(4-Ch lor oben zam ido)-3-deoxy-3-â-D-xylofu r an osyl]-
N6-cyclop en tyla d en in e (7b): mp 249-250.5 °C; 1H NMR
(DMSO-d6) δ 1.5-1.8 (m, 6H), 1.92 (br s, 2H) (cyclopentyl),
3.52 (m, H-5B′), 3.68 (m, H-5A′), 4.32 (app q, H-4′), 4.51 (br s,
cyclopentyl CH-NH), 4.61 (app q, H-3′), 4.78 (app q, H-2′), 5.30
(br s, 5′-OH), 5.86 (d, J ) 4.7 Hz, H-1′), 6.00 (d, J ) 4.8 Hz,
2′-OH), 7.64 (d, arom H-3,5), 7.90 (m, arom H-2,6, NH-
cyclopentyl), 8.15 (br s, H-2), 8.38 (s, H-8); 13C NMR (DMSO-
d6) δ 23.69, 32.21 (cyclopentyl), 57.37 (C-3′), 60.58 (C-5′), 77.71
(C-2′), 80.42 (C-4′), 89.98 (C-1′), 128.90, 129.34 (2 Co, 2 Cm),
133.36, 136.53 (Cipso, Cp), 140.59 (C-8), 152.40 (C-2), 154.73 (C-
6), 165.99 (CO); MS (LSIMS, thioglycerol) m/z 473 (M + H)+,
9-[3-Deoxy-3-(4-n it r ob en za m id o)-â-D-xylofu r a n osyl]-
1
N6-cyclop en tyla d en in e (7e): mp 235 °C slow dec; H NMR
(DMSO-d6) δ 1.5-1.8 (m, 6H), 1.93 (br s, 2H) (cyclopentyl),
3.45 (m, H-5B′), 3.68 (m, H-5A′), 4.32 (app q, H-4′), 4.50
(cyclopentyl CH-NH), 4.62 (app q, H-3′), 4.80 (app q, H-2′), 5.30
(br s, 5′-OH), 5.88 (d, J ) 4.7 Hz, H-1′), 6.02 (d, J ) 5.0 Hz,
2′-OH), 7.93 (d, NH-cyclopentyl), 8.10 (m, 3H, H-2, arom
H-2,6), 8.40 (d, arom H-3,5), 8.42 (s, H-2); 13C NMR (DMSO-
d6) δ 23.67, 32.20, 51.70 (cyclopentyl), 57.46 (C-3′), 60.54 (C-
5′), 77.63 (C-2′), 80.36 (C-4′), 90.00 (C-1′), 120.1 (C-5), 124.06
(2 Cm), 128.92 (2 Co), 140.30 (Cipso), 140.63 (C-8), 147.5 (C-4),
149.41 (Cp), 152.43 (C-2), 154.69 (C-6), 165.46 (CO); MS
(LSIMS, thioglycerol) m/z 506 (M + Na)+, 484 (M + H)+, 246
(s1), 232 (s2), 204 (B + 2H)+, 136 (B - cyclopentyl + 2H)+. Anal.
(C22H25N7O6) C, H, N.
9-[3-Deoxy-3-(3,4-d im eth ylben za m id o)-â-D-xylofu r a n o-
syl]-N6-cyclop en tyla d en in e (7f): 1H NMR (DMSO-d6) δ 1.5-
1.8 (m, 6H), 1.95 (br s, 2H) (cyclopentyl), 2.30 (s, 2CH3), 3.52
(m, H-5B′), 3.65 (m, H-5A′), 4.31 (app q, H-4′), 4.53 (br s,
cyclopentyl CH-NH), 4.61 (ddd, H-3′), 4.77 (app q, H-2′), 5.25
(dd, 5′-OH), 5.85 (d, J ) 4.4 Hz, H-1′), 5.99 (d, J ) 5 Hz, 2′-
OH), 7.31 (d), 7.60 (d) (arom H-5,6), 7.64 (s, arom H-2), 7.90
(d, NH-cyclopentyl), 8.15 (br s, H-2), 8.40 (s, H-8), 9.27 (d, J )
8.1 Hz, NHCO); 13C NMR (DMSO-d6) δ 19.39 (2Me), 23.51,
32.07, 51.62 (cyclopentyl), 57.25 (C-3′), 60.38 (C-5′), 77.90 (C-
2′), 80.45 (C-4′), 90.04 (C-1′), 120.04 (C-5), 124.64, 128.20,
129.57, 132.06, 136.45, 140.21 (aromatic C's), 140.44 (C-8),
147.60 (C-4), 152.11 (C-2), 154.58 (C-6), 166.89 (CO); MS
(LSIMS, thioglycerol) m/z 467 (M + H)+, 246 (s1), 232 (s2), 204
(B + 2H)+, 136 (B - cyclopentyl + 2H)+, 133 (COC6H4-3,4-
diMe)+. Anal. (C24H30N6O4‚1/2H2O) C, H, N.
9-[3-Deoxy-3-(3,4-d ich lor oben za m id o)-â-D-xylofu r a n o-
syl]-N6-cyclop en tyla d en in e (7g). 1H NMR (DMSO-d6) δ
1.5-1.8 (m, 6H), 1.97 (br s, 2H) (cyclopentyl), 3.52 (m, H-5B′),
3.66 (m, J 5A′,5B′ ) -12.3 Hz, H-5A′), 4.33 (m, H-4′), 4.53 (br s,
cyclopentyl CH-NH), 4.62 (app q, H-3′), 4.83 (app q, H-2′), 5.33
(dd, 5′-OH), 5.86 (d, J ) 5.0 Hz, H-1′), 5.97 (d, J ) 5.1 Hz,
2′-OH), 7.85 (s, 2H), 8.10 (s) (aromatic H’s), 7.93 (d, NH-
cyclopentyl), 8.17 (br s, H-2), 8.38 (s, H-8), 9.45 (d, J ) 7.9 Hz,
NHCO); 13C NMR (DMSO-d6) δ 23.51, 32.10, 51.60 (cyclopen-
tyl), 57.25 (C-3′), 60.41 (C-5′), 77.06 (C-2′), 80.03 (C-4′), 89.55
(C-1′), 120.01 (C-5), 127.57, 129.24, 130.98, 131.44, 134.32,

Non-Xanthine Adenosine A1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23 3771
134.78 (aromatic C’s), 140.31 (C-8), 147.74 (C-4), 152.16 (C-
2), 154.56 (C-6), 164.65 (CO); MS (LSIMS, thioglycerol) m/z
507 (M + H)+, 246 (s1), 232 (s2), 204 (B + 2H)+, 173 (COC6H4-
3,4-diCl)+, 136 (B - cyclopentyl + 2H)+. Anal. (C22H24N6O4-
Cl2‚1/2H2O) C, H, N.
lent isotropic displacement parameters, anisotropic displace-
ment parameters, bond lengths, and bond angles) (7 pages).
Ordering information is given on any current masthead page.
Refer en ces
9-(3-Deoxy-3-p h en yla ceta m id o-â-D-xylofu r a n osyl)-N6-
cyclop en tyla d en in e (7h ): Mp 110.5-112.5 °C; 1H NMR
(DMSO-d6) δ 1.5-1.8 (m, 6H), 1.95 (br s, 2H) (cyclopentyl),
3.40 (m, H-5B′), 3.52 (d, A of AB, J ) -13 Hz), 3.56 (m, H-5A′),
3.58 (d, B of AB, PhCH2), 4.21 (m, H-4′), 4.43 (app q, H-3′),
4.55 (br s, cyclopentyl CH-NH), 4.69 (app q, H-4′), 5.47 (dd,
5′-OH), 5.79 (d, J ) 5.5 Hz, H-1′), 5.89 (d, J ) 5.4 Hz, 2′-OH),
7.19-7.33 (m, 5H, Ph), 7.90 (d, NH-cyclopentyl), 8.25 (br s,
H-2), 8.33 (s, H-8), 8.78 (d, J ) 7.9 Hz, NHCO); 13C NMR
(DMSO-d6) δ 23.71, 32.24, 51.76 (cyclopentyl), 42.60 (COCH2),
56.13 (C-3′), 60.68 (C-5′), 76.70 (C-2′), 79.90 (C-4′), 89.30 (C-
1′), 120.18 (C-5), 126.65 (Cp), 128.47, 129.22 (2 Co, 2 Cm), 136.45
(Cipso), 140.45 (C-8), 147.91 (C-4), 152.39 (C-2), 154.73 (C-6),
170.78 (CO); MS (LSIMS, thioglycerol) m/z 475 (M + Na)+,
453 (M + H)+, 246 (s1), 232 (s2), 204 (B + 2H)+, 136 (B -
cyclopentyl + 2H)+, 119 (PhCH2CO)+. Anal. (C23H28N6O4) H,
N; C: calcd, 61.03; found, 60.22.
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9-[3-Deoxy-3-(3-p h en ylp r op ion a m id o)-â-D-xylofu r a n o-
syl]-N6-cyclop en tyla d en in e (7i): mp 103.5-105 °C; 1H NMR
(DMSO-d6) δ 1.48-1.82 (m, 6H), 1.96 (br s, 2H) (cyclopentyl),
2.54 (dd, 2H), 2.86 (app t, 2H, CO(CH2)2), 3.35 (m, H-5B′), 3.51
(m, H-5A′), 4.20 (m, H-4′), 4.44 (app q, H-3′), 4.53 (br s,
cyclopentyl CH-NH), 4.62 (app q, H-4′), 5.41 (dd, 5′-OH), 5.79
(d, J ) 5.4 Hz, H-1′), 5.87 (d, J ) 5.4 Hz, 2′-OH), 7.12-7.30
(m, 5H, Ph), 7.88 (d, NH-cyclopentyl), 8.22 (br s, H-2), 8.32 (s,
H-8), 8.60 (d, J ) 7.9 Hz, NHCO); 13C NMR (DMSO-d6) δ 23.72,
32.29, 51.78 (cyclopentyl), 31.35 (PhCH2), 37.19 (COCH2), 56.05
(C-3′), 60.63 (C-5′), 76.81 (C-2′), 79.94 (C-4′), 89.34 (C-1′),
120.18 (C-5), 126.12 (Cp), 128.47 (2 Co, 2 Cm), 140.41 (C-8),
141.34 (Cipso), 147.91 (C-4), 152.32 (C-2), 154.74 (C-6), 172.03
(CO); MS (LSIMS, thioglycerol) m/z 467 (M + H)+, 264 (M -
B)+, 246 (s1), 232 (s2), 204 (B + 2H)+, 136 (B - cyclopentyl +
2H)+. Anal. (C24H30N6O4) H, N; C: calcd, 61.77; found, 62.70.
9-[3-Deoxy-3-(4-ph en ylbu tyr am ido)-â-D-xylofu r an osyl]-
1
N6-cyclop en tyla d en in e (7j): mp 91.5 °C; H NMR (DMSO-
d6) δ 1.48-1.78 (m, 6H), 1.95 (br s, 2H) (cyclopentyl), 1.84 (m,
2H), 2.23 (m, 2H), 2.60 (t, 2H) (3 CH2 of butyramide), 3.49 (m,
H-5B′), 3.60 (m, H-5A′), 4.24 (m, H-4′), 4.44 (app q, H-3′), 4.52
(br s, cyclopentyl CH-NH), 4.65 (app q, H-4′), 5.39 (dd, 5′-OH),
5.80 (d, J ) 5.2 Hz, H-1′), 5.89 (d, J ) 5.3 Hz, 2′-OH), 7.14-
7.22 (m, 3H), 7.28 (t, 2H, Ph), 7.89 (d, J ) 7.2 Hz, NH-
cyclopentyl), 8.18 (br s, H-2), 8.35 (s, H-8), 8.69 (d, J ) 7.9 Hz,
NHCO); 13C NMR (DMSO-d6) δ 23.71, 32.26, 51.80 (cyclopen-
tyl), 27.52, 34.87, 35.16 (3 CH2 of butyramide), 56.18 (C-3′),
60.70 (C-5′), 77.11 (C-2′), 80.07 (C-4′), 89.48 (C-1′), 120.18 (C-
5), 125.99 (Cp), 128.53 (2 Co, 2 Cm), 140.47 (C-8), 141.92 (Cipso),
147.93 (C-4), 152.31 (C-2), 154.74 (C-6), 172.51 (CO); MS
(LSIMS, thioglycerol) m/z 481 (M + H)+, 278 (M - B)+, 246
(s1), 232 (s2), 204 (B + 2H)+, 136 (B - cyclopentyl + 2H)+. Anal.
(C25H32N6O4) H, N; C: calcd, 62.47; found, 61.93.
9-[3-Deoxy-3-(4-cycloh exylb u t yr a m id o)-â-D-xylofu r a -
n osyl]-N6-cyclop en tyla d en in e (7l): mp 110 °C dec; 1H NMR
(DMSO-d6) δ 0.80 (dd, 2H), 1.1-1.2 (m, 6H), 1.5-1.8 (m, 13H),
1.92 (br s, 2H), 2.18 (m, 2H) ((CH2)3C6H11), cyclopentyl), 3.47
(m, H-5B′), 3.57 (m, J 5A′,5B′ ) -12.3 Hz, H-5A′), 4.21 (m, H-4′),
4.40 (app q, H-3′), 4.53 (br s, cyclopentyl CH-NH), 4.61 (app
q, H-2′), 5.35 (dd, 5′-OH), 5.78 (d, J ) 5.1 Hz, H-1′), 5.86 (d, J
) 6.3 Hz, 2′-OH), 7.90 (d, NH-cyclopentyl), 8.15 (s, H-2), 8.35
(s, H-8), 8.61 (d, J ) 8.0 Hz, 3′-NH); 13C NMR (DMSO-d6) δ
22.75, 23.52, 25.81, 26.20, 32.11, 32.77, 32.82, 35.79, 36.42,
36.77, 51.62 ((CH2)3C6H11, cyclopentyl), 56.04 (C-3′), 60.44 (C-
5′), 77.11 (C-2′), 79.93 (C-4′), 89.37 (C-1′), 140.18 (C-8), 152.08
(C-2), 154.57 (C-6), 172.55 (CO); MS (LSIMS, thioglycerol) m/z
487 (M + H)+, 246 (s1), 232 (s2), 204 (B + 2H)+, 136 (B -
cyclopentyl + 2H)+. Anal. (C25H38N6O4) C, H, N.
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J M970176K