Nucleosides and nucleotides. 200. Reinvestigation of 5′-N-ethylcarboxamidoadenosine derivatives: Structure-activity relationships for P3 purinoceptor-like proteins

Article abstract of DOI:10.1021/jm000150k

The non-P₁ and non-P₂ muscle relaxant effect of ATP in rabbit thoracic aorta has recently been attributed to a putative P₃ purinoceptor, which is activated by either adenosine or ATP. Since the physiological roles of this

Full text of DOI:10.1021/jm000150k

208
J . Med. Chem. 2001, 44, 208-214
Nu cleosid es a n d Nu cleotid es. 200. Rein vestiga tion of
5′-N-Eth ylca r boxa m id oa d en osin e Der iva tives: Str u ctu r e-Activity Rela tion sh ip s
for P 3 P u r in ocep tor -lik e P r otein s1
Takashi Umino,† Kazuaki Yoshioka,‡ Yoshiko Saitoh,‡ Noriaki Minakawa,† Hiroyasu Nakata,‡ and
Akira Matsuda*,†
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, J apan,
and Department of Molecular and Cellular Neurobiology, Tokyo Metropolitan Institute for Neuroscience,
Fuchu, Tokyo 183-8526, J apan
Received April 3, 2000
The non-P1 and non-P2 muscle relaxant effect of ATP in rabbit thoracic aorta has recently
been attributed to a putative P3 purinoceptor, which is activated by either adenosine or ATP.
Since the physiological roles of this putative P3 purinoceptor and of a new [3H]-5′-N-
ethylcarboxamidoadenosine (NECA)-binding protein from rat brain membranes called P3
purinoceptor-like protein (P3LP), due to its ligand specificity, have not been fully elucidated,
we needed a specific ligand to obtain further information about the receptor. We examined the
structure-activity relationship (SAR) of various 5′-N-substituted-carboxamidoadenosine deriva-
tives toward P3LP and discovered a hydrophobic binding region near the 5′-N-substituted-
carboxamide group. From the linear alkyl N-substituted derivatives, the N-n-pentyl derivative
10 was found to be the most potent ligand with a Ki value of 12 nM. In the series of the
N-cycloalkyl derivatives, the N-cyclohexyl derivative 27 was the strongest ligand with a Ki
value of 18 nM. On the other hand, the N-substituents having branched alkyl side chains and
bulky cycloalkyl groups did not show any potent affinities for P3LP. Therefore, the hydrophobic
pocket accommodates approximately a 10-carbon-atom-long linear alkyl side chain, while a
considerably stronger hydrophobic binding region of about a 5-carbon-atom-long depth exists
near the nitrogen atom of the amide group. This pocket also allows substitution with bulky
hydrophobic groups since the 5′-N-cycloalkyl derivatives have high affinities. We also examined
the receptor selectivity for the selected nucleosides 10 and 27 with 1 [9-(6,7-dideoxy-â-D-allo-
hept-5-ynofuranosyl)adenine, HAK2701] and NECA versus P1 purinoceptor subtypes, such as
adenosine A1, A2A, A2B, and A3 receptors, and found that 27 is the most selective ligand for
P3LP.
In tr od u ction
using various classical ligands.5-17 Electrically evoked
release of noradrenaline in rat caudal arteries was
reported to be activated by 2-chloroadenosine as well
as ATP.5 The muscle relaxant effect of ATP in rabbit
thoracic aortas was attributed to a putative P3 pu-
rinoceptor, which is activated by either adenosine or
ATP.9,12 Facilitation of norepinephrine release in the
adrenergic nerves of rabbit ear arteries by either 2-chlo-
roadenosine or ATP was also reported to be caused by
a putative P3 purinoceptor.13 Induction of K+ currents
in the follicle cell layer of Xenopus oocytes was also
attributed to non-P1 and non-P2 purinoceptors.16 Saitoh
and Nakata purified a new [3H]-5′-N-ethylcarboxami-
doadenosine (NECA)-binding protein from rat brain
membranes17 and demonstrated that its ligand specific-
ity followed the order NECA > adenosine g AMP >
ADP > inosine > ATP > N6-cyclopentyladenosine .
2-chloroadenosine, and most xanthines were inactive.
This result is very similar to the ranking of potency
toward the muscle receptor reported by Chinellato et
al. (NECA > adenosine > ATP)9,12 but is slightly
different from the relative order of potency in adrenergic
nerves of rat caudal arteries (2-chloroadenosine > ATP
> adenosine)5 and in the follicle cell layer of Xenopus
oocytes (ATP > adenosine > â,γ-methylene-ATP).16
Adenine nucleosides and nucleotides exert a large
variety of physiological responses in various tissues and
cells via specific receptors, i.e., purinoceptors, on the cell
surface membranes.2-4 Purinoceptors have been clas-
sified as P1 and P2 based on their pharmacological
properties. P1 purinoceptors, which are usually called
adenosine receptors, are selective for adenosine and its
analogues, while P2 purinoceptors are specific for ad-
enine nucleotides such as ATP and their analogues. P1
purinoceptors are subclassified as A1, A2A, A2B, and A3
adenosine receptors. P2 purinoceptors are also further
divided into several subtypes. Although the presence of
such purinoceptor subtypes explains many of the func-
tions of adenine nucleosides and nucleotides, it may be
necessary and helpful to identify additional subtypes
to fully explain the functional roles of these substances
in various tissues or cells.
Evidence for the presence of non-P1 and non-P2
purinoceptors in several tissues has been accumulated
* To whom correspondence and reprint requests should be ad-
dressed. Phone: +81-11-706-3228. Fax: +81-11-706-4980. E-mail:
matuda@pharm.hokudai.ac.jp.
† Hokkaido University.
‡ Tokyo Metropolitan Institute for Neuroscience.
10.1021/jm000150k CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/02/2000

5′-N-Ethylcarboxamidoadenosine Derivatives
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 2 209
Ta ble 1. P3LP Binding Activity of Various NECA Analoguesa
compd
Rb
Ki (nM)
compd
Rb
Ki (nM)
compd
Rb
Ki (nM)
5
6
7
8
9
10
11
12
13
14
15
16
17
H
Me
Et
n-Pr
n-Bu
n-Pent
n-Hex
n-Hept
n-Oct
n-Non
n-Dec
n-Undec
n-Dodec
64 ( 9
51 ( 8
37 ( 3
31 ( 4
17 ( 3
12 ( 2
19 ( 5
20 ( 3
21 ( 3
31 ( 4
27 ( 7
123 ( 34
163 ( 29
18
19
20
21
22
23
24
25
26
27
28
29
30
s-Bu*
t-Bu
198 ( 27
6850 ( 1610
167 ( 42
29 ( 10
46 ( 10
10 ( 4
31
32
33
34
35
36
37
38
39
40
41
42
trans-4-Me-cHex
2-Me-cHex*
2-norbornyl*
1-adamantyl
2-adamantyl
3-noradamantyl
HO
MeO
EtO
i-BuO
Bn
12.9 ( 3
69.5 ( 14
640 ( 60
1040 ( 200
2000 ( 600
833 ( 112
41 ( 10
H2N(CH2)2
H2N(CH2)8
AcHN(CH2)2
AcHN(CH2)8
cPr
cBu
cPent
cHex
cHept
96 ( 11
88 ( 12
49 ( 8
58 ( 13
67 ( 10
18 ( 2
20 ( 9
22 ( 5
42 ( 4
cOct
cis-4-Me-cHex
23 ( 5
3,4-(OMe)2Bn
140 ( 35
55.6 ( 12
a
P3LP binding activity to [3H]NECA (40 nM) was determined as described previously. P3LP was partially purified by hydroxylapatite
chromatography from a CHAPS-solubilized preparation of rat brain membranes. A1, A2A, A2B and A3 adenosine receptors and adenotin
b
were not present in this preparation. Ki values are expressed as mean ( SEM (n ) 3). See Scheme 1 for R.
Sch em e 1a
Therefore, this [3H]NECA-binding protein from rat
brain membranes was thought to be a subtype of
putative P3 purinoceptors or P3 purinoceptor-like pro-
teins (P3LP).
On the basis of these results, we became interested
in understanding the functions of the putative P3
purinoceptors or P3LP. However, further characteriza-
tion is hampered by the lack of specific ligands for the
putative P3 purinoceptors. We previously reported that
9-(6,7-dideoxy-â-D-allo-hept-5-ynofuranosyl)adenine (HAK
2701, 1) was a potent and relatively selective ligand for
a
(a) p-Nitrophenol, 1-[3-(dimethylamino)propyl]-3-ethylcarbo-
diimide‚HCl, DMF; (b) RNH2 or R′ONH2; (c) 80% aq TFA.
P3LP.18 During the course of the structure-activity
relationship (SAR) study, we also found that the 5′-N-
alkyl substituents of the carboxamide moiety of 5′-
carboxamidoadenosine derivatives affected P3LP bind-
ing affinity.18 The ligand specificity was shown to follow
the order NECA > 5′-N-methylcarboxamidoadenosine
> 5′-carboxamidoadenosine . 5′-N,N-dimethylcarboxa-
midoadenosine. The larger the alkyl group at the 5′-N-
position, the better the affinity. This finding strongly
suggested the presence of a hydrophobic pocket around
the 5′-position of NECA. Herein we describe the struc-
tural requirements of various 5′-N-substituted-carboxa-
midoadenosine analogues with regard to P3LP binding
to find new selective ligands for P3LP and show a
descriptive rendering of the shape of the hydrophobic
pocket.
variety of 5′-N-monosubstituted-carboxamidoadenosines
(5-42, Scheme 1 and Table 1).
Biologica l Eva lu a tion a n d Discu ssion
P3LP binding assays were carried out using P3LP that
was partially purified from rat brain membranes by [3H]-
NECA (40 nM) in the presence of various concentrations
of NECA analogues.17 This preparation does not contain
adenosine receptors (A1, A2A, A2B, and A3) and adenotin
1 and 2. Ki values were calculated using Graph Pad
software (ISI Software), and the results are summarized
in Table 1.
Previously, we found that 5′-carboxamidoadenosine
(5), 5′-N-methylcarboxamidoadenosine (6), and NECA
(7) were good ligands with Ki values of 64, 51, and 37
nM, respectively.18 When the length of the linear 5′-N-
alkyl chain was increased, the affinity was proportion-
ally enhanced up to the 5′-N-n-pentyl derivative 10,
which was 3-fold more potent than NECA (7) (Figure
1) with a Ki value of 12 nM. Increasing the side chain
length to n-decyl did not decrease the affinity dramati-
cally; the Ki value of the 5′-N-n-decyl derivative 15 (27
nM) was similar to that of NECA (7). However, the
n-undecyl 16 and the n-dodecyl 17 derivatives showed
10- and 14-fold less affinity than 10. Interestingly, the
5′-N-aminoethyl derivative 20 had a Ki value of 167 nM
Ch em istr y
Various 5′-N-substituted analogues of 5′-carboxami-
doadenosine have been prepared from 2′,3′-O-isoprop-
ylideneadenosine-5′-carboxylic acid (2), which was readily
obtained from adenosine in two steps.19-23 Compound
2 was converted into its p-nitrophenyl ester 3, which,
without isolation, was treated with an appropriate
monosubstituted amine or a hydroxylamine derivative
to give the 5′-N-substituted-carboxamido-2′,3′-O-isoprop-
ylideneadenosine derivative 4. Compound 4 was then
treated with 80% aqueous trifluoroacetic acid to give a

210 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 2
Umino et al.
group in 30 should be larger than that of the equatorial
methyl group in 31. The distance between the amide
nitrogen and the terminal methyl group is similar to
that of the 5′-N-n-pentyl group in 10. Therefore, the
differences between 30 and 31 would be related to the
affinity for P3LP. Moreover, the analogues having bulky
5′-N-substituents such as 33-36 showed much less
affinity for P3LP. These data are consistent with the
above-mentioned data for compounds 18 and 19.
We have shown that the acidic proton of the 5′-amide
group is essential for binding to P3LP. A hydroxylamino
or alkoxyamino group instead of an alkylamino group
in the amide function would increase the acidity of the
NH group. However, the derivatives 37-42 did not show
clear SARs as did the N-alkyl derivatives.
On the basis of these SARs, we propose the following
guidelines for recognition of the 5′-N-substituted-car-
boxamidoadenosine derivatives by P3LP: (1) For 5′-N-
substituents, there is a hydrophobic binding region to
accommodate the linear 5′-N-alkyl side chain and the
cycloalkyl groups with a certain depth and width. The
depth of the region is about 10-carbon-atoms-long;
within about a five-carbon-atom-long depth from the
nitrogen of the amide group, there is a relatively strong
hydrophobic region. However, near the nitrogen atom
of the amide group, the receptor only accommodates
linear alkyl substituents but not branched alkyl sub-
stituents. Therefore, the region for the side chain must
be narrow but can accept cycloalkyl groups. (2) Acidic
protons such as the 5′-OH group in 1 and the NH group
in the 5′-N-substituted-carboxamidoadenosines are
needed to bind the receptor.
F igu r e 1. Effects of the carbon number of the linear alkyl
side chain in compounds 5-17 (b) and the ring size of the
cycloalkane side chain in compounds 24-29 (O) toward P3LP
binding.
versus P3LP, although the length of the side chain is
similar to an n-propyl group, while the 5′-N-aminooctyl
derivative 21 acted as a potent ligand with a Ki value
of 29 nM. After acetylation of the terminal amino groups
of 20 and 21, the affinities of the products 22 and 23
were increased to about 4- and 3-fold, respectively. On
the other hand, compounds bearing 5′-N-branched alkyl
chains, such as the secondary butyl derivative 18 (Ki )
198 nM) and the tertiary butyl derivative 19 (Ki ) 6850
nM) had much less affinity for P3LP, although the
length of the alkyl chains is similar to that of ethyl and
propyl groups. From these results, the hydrophobic
pocket accommodates up to 10 carbon atoms in the
linear alkyl side chain of the 5′-N-substituents in the
NECA derivatives, while a relatively strong hydrophobic
binding region of about a 5-carbon-atom-long depth
exists near the nitrogen atom of the amide group. Near
the 5′-NH region, there would be a narrow hydrophobic
interaction region. The presence of the NH group is
essential for affinity for P3LP, because N,N-dimethyl-
carboxamidoadenosine did not bind well with a Ki value
of 21 000 nM.
We next compared the affinities of various 5′-N-
cycloalkyl-substituted analogues of NECA. As shown in
Table 1, the N-cyclohexyl derivative 27 had the most
potent affinity in the series with a Ki value of 18 nM.
The analogues having smaller and larger rings than
cyclohexane showed less potent affinities than 27 (Fig-
ure 1). Furthermore, the 5′-N-trans-4-methylcyclohexyl
derivative 31 was more potent (Ki ) 12.9 nM) than the
5′-N-cis-4-methylcyclohexyl derivative 30 with a Ki
value of 55.6 nM. Compound 31 is slightly more potent
than the cyclohexyl derivative 27, and its potency is
similar to that of the n-pentyl derivative 10. On the
basis of these observations, the 4-methylcyclohexane
moiety in compounds 30 and 31 would exist in a chair
form rather than in a boat form, where the methyl group
should be in the axial orientation in the cis-analogue
30 but in the equatorial orientation in the trans-
analogue 31. The steric bulkiness of the axial methyl
We next compared the receptor selectivity for selected
nucleosides 10 and 27 with 1 and NECA versus P1
purinoceptor subtypes, such as adenosine A1, A2A, A2B
,
and A3 receptors. As described in Table 2, NECA showed
ligand selectivity for A2B receptors but almost none
versus A1, A2A, and A3 receptors. On the other hand, 1
showed much better selectivity versus all of the adeno-
sine receptor subtypes than NECA. However, the newly
synthesized compound 27 is a more selective ligand for
A1, A2A, and A2B than 1, since they have almost the same
affinities for P3LP. Versus the adenosine A3 receptor,
compound 27 has about 20-fold less selectivity than 1,
but both affinities would be entirely negligible compared
to the affinity for P3LP. Compound 10 is also selective,
but still has NECA-like affinity for A1 and A2A receptors.
Therefore, compound 27 is the most selective ligand for
P3LP.
Because 2-[[4-(2-carboxyethyl)phenethyl]amino]-5′-N-
ethylcarboxamidoadenosine (CGS21680) did not show
any binding affinity to the partially purified P3LP
preparation, P3LP seems not to be related to the atypical
adenosine binding site, which is responsive to [3H]-
CGS21680 proposed by Cunha et al.26
In summary, we have studied the SAR of 5′-N-
substituted-carboxamidoadenosine derivatives versus
P3LP. We found a hydrophobic binding pocket around
the N-substituted-carboxamide group. Further studies
will be needed to elucidate the SARs of adenosine
analogues versus P3LP in greater detail, particularly
with regard to the pharmacological activity of 27.

5′-N-Ethylcarboxamidoadenosine Derivatives
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 2 211
Ta ble 2. Affinities of Selected Ligands to Adenosine A1, A2A, A2B, and A3 Receptors and to P3LPa
c
c
d
e
compd
Ki (nM) P3LPb
Ki (nM) A1
979 ( 18
A1/P3LP
Ki (nM) A2A
A2A/P3LP
agonist activity A2B
Ki (nM) A3
5560 ( 30
A3/P3LP
10
27
1
12.2 ( 1.6
18.2 ( 2.1
20 ( 1.4
80.2
275
44.9
0.29
605 ( 95
2500 ( 90
2110 ( 160
49.6
137
105
3.4% at 100 µM
1.9% at 100 µM
10% at 100 µM
100% at 100 µM
456
830
15500
15.3
5020 ( 240
897 ( 14
7.7 ( 1.9
15100 ( 300
310000 ( 43000
412 ( 1
NECA
27 ( 3.8
4.13 ( 0.88
0.152
a
b
Ki values are expressed as mean ( SEM (n ) 3). See Table 1 for the binding assay. c The activities of A1 and A2A adenosine receptors
were measured by binding [3H]8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 2 nM) and [3H]2-[[4-(2-carboxyethyl)phenethyl]amino]-5′-N-
ethylcarboxamidoadenosine (CGS21680, 6 nM) to rat brain membranes, respectively.24,25 Because specific radiolabeled ligands for A2B
d
adenosine receptor binding were not commercially available at this time, A2B adenosine receptor agonist activity was determined by
measuring cAMP production in CHO cells transfected with rat A2B adenosine receptor cDNA. The activity of each compound at 100 µM
is expressed as the percentage of NECA-induced activity. It was also confirmed that no antagonist activity of each test compound for A2B
adenosine receptor was detected because NECA (10 µM)-induced cAMP production was not inhibited at all by addition of each test compound
(100 µM) (data not shown). e The activity of A3 adenosine receptor was measured by binding [125I]N6-(3-iodophenyl)-5′-(N-methylcarboxa-
mido)adenosine (IB-MECA, 0.3 nM) to cell membranes prepared from CHO cells transfected with rat A3 adenosine receptor in the presence
of 100 nM DPCPX and 100 µM 5′-adenylimidodiphosphate (AppNHp) (A) and in the presence of 100 µM DPCPX, 100 µM AppNHp and
10 nM IB-MECA (B). Specific A3 adenosine receptor activity was calculated from the difference between the binding activity in (A) and
(B).
(s, 1 H, H-2 or H-8), 8.35 (s, 1 H, H-2 or H-8). Anal.
Exp er im en ta l Section
(C16H24N6O4‚1/2H2O) C, H, N.
Melting points were measured on a Yanagimoto MP-3
micromelting point apparatus (Yanagimoto, J apan) and are
uncorrected. Fast atom bombardment mass spectrometry
(FAB-MS) was performed on a J EOL J MS-HX110 instrument
at an ionizing voltage of 70 eV. The 1H NMR spectra were
recorded on a J EOL J NM-GX 270 (270 MHz) or Bruker ARX
500 (500 MHz) spectrometer with tetramethylsilane as an
internal standard. Chemical shifts are reported in parts per
million (δ), and signals are expressed as s (singlet), d (doublet),
t (triplet), m (multiplet), or br (broad). All exchangeable
protons were detected by disappearance on the addition of D2O.
UV absorption spectra were recorded with a Shimadzu UV-
240 spectrophotometer. IR spectra were recorded with a J EOL
A-102 spectrometer. TLC was done on Merck Kieselgel F254
precoated plates (Merck, Germany). The silica gel used for
column chromatography was YMC gel 60A (70-230 mesh)
(YMC Co., Ltd., J apan).
Gen er a l P r oced u r e for P r ep a r a tion of 1-(Ad en in -9-yl)-
1-d eoxy-N-et h yl-â-D-r ib ofu r a n u r on a m id e (NE CA) De-
r iva t ives. p-Nitrophenol (167 mg, 1.2 mmol) and 1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (211
mg, 1.1 mmol) were added to a suspension of 2′,3′-O-isoprop-
ylideneadenosine-5′-carboxylic acid (2;19 321 mg, 1.0 mmol) in
dry DMF (5 mL). The reaction mixture was stirred for 3 h at
room temperature. Each amine or hydroxylamine was added
to the reaction mixture, which was further stirred for 1 h at
room temperature. The reaction was monitored by TLC
(EtOH-CHCl3, 1:15). The mixture was concentrated in vacuo,
and the residue was partitioned between EtOAc and H2O. The
organic layer was washed with H2O, followed by brine. The
organic layer was dried (Na2SO4) and concentrated to dryness.
The residue was dissolved in 80% aqueous TFA (8 mL), and
the solution was stirred for 1-3 h at room temperature. The
volitile was removed in vacuo, and the residue was coevapo-
lated several times with EtOH and purified by silica gel
column chromatography.
1-(Aden in -9-yl)-1-deoxy-N-n -h eptyl-â-D-r ibofu r an u r on a-
m id e (12): yield 231 mg (60%); mp 105-106 °C (crystallized
from EtOH-hexane); FAB-MS m/z 379 (MH+); 1H NMR
(DMSO-d6 + D2O) 0.81 (t, 3 H, CH3CH2, J ) 6.6 Hz), 1.20-
1.46 (m, 10 H, CH2 × 5), 3.18 (t, 2 H, CH2NH, J ) 6.6 Hz),
4.09 (d, 1 H, H-3′, J 3′,2′ ) 4.6 Hz), 4.29 (s, 1 H, H-4′), 4.57 (dd,
1 H, H-2′, J 2′,1′ ) 7.9, J 2′,3′ ) 4.6 Hz), 5.94 (d, 1 H, H-1′, J 1′,2′
)
7.9 Hz), 8.15 (s, 1 H, H-2 or H-8), 8.35 (s, 1 H, H-2 or H-8).
Anal. (C17H26N6O4‚1/2H2O) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-n -octyl-â-D-r ibofu r a n u r on a -
m id e (13): yield 357 mg (87%); mp 108-109 °C (crystallized
from EtOH); EI-MS m/z 392 (M+); 1H NMR (DMSO-d6 + D2O)
0.84 (dd, 3 H, CH3CH2, J ) 7.3, 5.9 Hz), 1.22-1.47 (m, 12 H,
CH2 × 6), 3.20 (dd, 2 H, CH2NH, J ) 6.6, 13.2 Hz), 4.12 (dd,
1 H, H-3′, J 3′,2′ ) 4.6, J 3′,4′ )1.3 Hz), 4.32 (d, 1 H, H-4′, J 4′,3′
)
1.3 Hz), 4.60 (dd, 1 H, H-2′, J 2′,1′ ) 7.9, J 2′,3′ ) 4.6 Hz), 5.95 (d,
1 H, H-1′, J 1′,2′ ) 7.9 Hz), 8.19 (s, 1 H, H-2 or H-8), 8.39 (s, 1H,
H-2 or H-8). Anal. (C18H28N6O4‚H2O) C, H, N.
1-(Ad en in -9-yl)-1-deoxy-N-n -n on yl-â-D-r ibofu r a n u r on a -
m id e (14): yield 399 mg (97%); mp 106-107 °C (crystallized
from MeOH); FAB-MS m/z 407 (MH+); 1H NMR (DMSO-d6
+
D2O) 0.80 (t, 3 H, CH3CH2, J ) 6.6 Hz), 1.18-1.44 (m, 14 H,
CH2 × 7), 3.14 (t, 2 H, CH2NH, J ) 6.6 Hz), 4.12 (dd, 1 H,
H-3′, J 3′,2′ ) 4.6, J 3′,4′ ) 1.3 Hz), 4.32 (d, 1 H, H-4′, J 4′,3′ ) 1.3
Hz), 4.56 (dd, 1 H, H-2′, J 2′,1′ ) 7.3, J 2′,3′ ) 4.6 Hz), 5.97 (d, 1
H, H-1′, J 1′,2′ ) 7.3 Hz), 8.29 (s, 1 H, H-2 or H-8), 8.54 (s, 1 H,
H-2 or H-8). Anal. (C19H30N6O4‚1/3H2O) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-n -d ecyl-â-D-r ibofu r a n u r on a -
m id e (15): yield 399 mg (94%); mp 124-125 °C (crystallized
from MeOH); FAB-MS m/z 421 (MH+); 1H NMR (DMSO-d6
+
D2O) 0.81 (t, 3 H, CH3CH2, J ) 6.6 Hz), 1.19-1.45 (m, 16 H,
CH2 × 8), 3.14 (t, 2 H, CH2NH, J ) 6.6 Hz), 4.10 (dd, 1 H,
H-3′, J 3′,2′ ) 4.6, J 3′,4′ ) 1.3 Hz), 4.30 (d, 1 H, H-4′, J 4′,3′ ) 1.3
Hz), 4.57 (dd, 1 H, H-2′, J 2′,1′ ) 7.3, J 2′,3′ ) 4.6 Hz), 5.95 (d, 1
H, H-1′, J 1′,2′ ) 7.3 Hz), 8.20 (s, 1 H, H-2 or H-8), 8.43 (s, 1 H,
H-2 or H-8). Anal. (C20H32N6O4‚1/5H2O) C, H, N.
1-(Aden in -9-yl)-1-deoxy-N-n -pen tyl-â-D-r ibofu r an u r on a-
m id e (10): yield 289 mg (82%); mp 117-118 °C (crystallized
1-(Ad e n in -9-yl)-1-d e oxy-N -n -u n d e cyl-â-D-r ib ofu r a n -
u r on a m id e (16): yield 416 mg (95%); mp 103-104 °C
(crystallized from aqueous MeOH); FAB-MS m/z 435 (MH+);
1H NMR (DMSO-d6 + D2O) 0.82 (t, 3 H, CH3CH2, J ) 6.6 Hz),
1.19-1.46 (m, 18 H, CH2 × 9), 3.17 (t, 2 H, CH2NH, J ) 6.6
Hz), 4.10 (d, 1 H, H-3′, J 3′,2′ ) 4.6 Hz), 4.30 (s, 1 H, H-4′), 4.57
(dd, 1 H, H-2′, J 2′,1′ ) 7.3, J 2′,3′ ) 4.6 Hz), 5.94 (d, 1 H, H-1′,
J 1′,2′ ) 7.3 Hz), 8.18 (s, 1 H, H-2 or H-8), 8.39 (s, 1 H, H-2 or
H-8). Anal. (C21H34N6O4‚1/10H2O) C, H, N.
1-(Ad e n in -9-yl)-1-d e oxy-N -n -d od e cyl-â-D-r ib ofu r a n -
u r on a m id e (17): yield 352 mg (72%); mp 144-146 °C
(crystallized from aqueous MeOH); FAB-MS m/z 449 (MH+);
1H NMR (DMSO-d6 + D2O) 0.82 (t, 3 H, CH3CH2, J ) 6.6 Hz),
1.17-1.44 (m, 20 H, CH2 × 10), 3.16 (t, 2 H, CH2NH, J ) 6.6
Hz), 4.10 (d, 1 H, H-3′, J 3′,2′ ) 4.6 Hz), 4.30 (s, 1 H, H-4′), 4.57
(dd, 1 H, H-2′, J 2′,1′ ) 7.3, J 2′,3′ ) 4.6 Hz), 5.94 (d, 1 H, H-1′,
from 2-propanol); EI-MS m/z 350 (M+); 1H NMR (DMSO-d6
+
D2O) 0.82 (t, 3 H, CH3CH2, J ) 6.6 Hz), 1.20-1.50 (m, 6 H,
CH2 × 3), 3.17 (dd, 2 H, CH2NH, J ) 6.6, J ) 13.2 Hz), 4.10
(dd, 1 H, H-3′, J 3′,2′ ) 4.6, J 3′,4′ ) 1.3 Hz), 4.30 (d, 1 H, H-4′,
J 4′,3′ ) 1.3 Hz), 4.59 (dd, 1 H, H-2′, J 2′,1′ ) 7.3, J 2′,3′ ) 4.6 Hz),
5.93 (d, 1 H, H-1′, J 1′,2′ ) 7.3 Hz), 8.16 (s, 1 H, H-2 or H-8),
8.35 (s, 1 H, H-2 or H-8). Anal. (C15H22N6O4‚1/5H2O) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-n -h exyl-â-D-r ibofu r a n u r on a -
m id e (11): yield 245 mg (66%); mp 144-146 °C (crystallized
from EtOH-hexane) (lit.20 104-106 °C); FAB-MS m/z 365
(MH+); 1H NMR (DMSO-d6 + D2O) 0.81 (t, 3 H, CH3CH2, J )
6.6 Hz), 1.22-1.47 (m, 8 H, CH2 × 4), 3.17 (dd, 2 H, CH2NH,
J ) 6.6 J ) 13.2 Hz), 4.09 (dd, 1 H, H-3′, J 3′,2′ ) 4.6, J 3′,4′ )1.3
Hz), 4.29 (d, 1 H, H-4′, J 4′,3′ ) 1.3 Hz), 4.59 (dd, 1 H, H-2′, J 2′,1′
) 7.9, J 2′,3′ ) 4.6 Hz), 5.92 (d, 1 H, H-1′, J 1′,2′ ) 7.9 Hz), 8.15

212 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 2
Umino et al.
J 1′,2′ ) 7.3 Hz), 8.19 (s, 1 H, H-2 or H-8), 8.40 (s, 1 H, H-2 or
H-8). Anal. (C22H36N6O4) C, H, N.
u r on a m id e (26): yield 163 mg (47%); mp 199-200 °C
(crystallized from MeOH) (lit.20 mp 165-170 °C); FAB-MS m/z
349 (MH+); 1H NMR (DMSO-d6 + D2O) 1.28-1.86 (m, 8 H,
1-(Aden in -9-yl)-1-deoxy-N-sec-bu tyl-â-D-r ibofu r an u r on a-
m id e (18): yield 311 mg (93%, mixture of two diastereomers,
ratio 1:1); mp 156-157 °C (crystallized from 2-propanol-
hexane); FAB-MS m/z 337 (MH+); 1H NMR (DMSO-d6 + D2O)
0.76 (t, 1.5 H, CH3, J ) 7.3 Hz), 0.84 (t, 1.5 H, CH3, J ) 7.3
Hz), 1.05 (d, 1.5 H, CH3, J ) 6.6 Hz), 1.11 (d, 1.5 H, CH3, J )
6.6 Hz), 1.29-1.57 (m, 2 H, CH2), 3.70-3.86 (m, 1 H, CHNH),
4.09 (m, 1 H, H-3′), 4.29 (m, 1 H, H-4′), 4.56-4.62 (m, 1 H,
H-2′), 5.76 (m, 1 H, H-1′), 8.13 (s, 0.5 H, H-2 or H-8), 8.14 (s,
0.5 H, H-2 or H-8), 8.35 (s, 0.5 H, H-2 or H-8), 8.38 (s, 0.5 H,
H-2 or H-8). Anal. (C14H20N6O4) C, H, N.
1-(Ad e n in -9-yl)-1-d e oxy-N -t er t -b u t yl-â-D-r ib ofu r a n -
u r on a m id e (19): yield 320 mg (95%); mp 135-136 °C
(crystallized from aqueous MeOH) (lit.23 140 °C); FAB-MS m/z
337 (MH+); 1H NMR (DMSO-d6 + D2O) 1.28 (s, 9 H, CH3 × 3),
4.11 (dd, 1 H, H-3′, J 3′,2′ ) 4.5, J 3′,4′ ) 1.4 Hz), 4.23 (d, 1 H,
H-4′, J 4′,3′ ) 1.4 Hz), 4.66 (dd, 1 H, H-2′, J 2′,1′ ) 7.3, J 2′,3′ ) 4.5
Hz), 5.92 (d, 1 H, H-1′, J 1′,2′ ) 7.3 Hz), 8.13 (s, 1 H, H-2 or
H-8), 8.40 (s, 1 H, H-2 or H-8). Anal. (C14H20N6O4‚1/10H2O) C,
H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-a m in oet h yl-â-D-r ib ofu r a n -
u r on a m id e (20): yield 363 mg (92%, white solid); FAB-MS
m/z 324 (MH+); 1H NMR (DMSO-d6 + D2O) 2.87 (dd, 2 H, CH2-
CH2, J ) 5.9, J ) 10.6 Hz), 3.37 (dd, 2 H, CH2CH2, J ) 5.9, J
) 10.6 Hz), 4.26 (d, 1 H, H-3′, J 3′,2′ ) 4.6 Hz), 4.39 (s, 1 H,
H-4′), 4.63 (dd, 1 H, H-2′, J 2′,1′ ) 6.6, J 2′,3′ ) 4.6 Hz), 6.03 (d, 1
H, H-1′, J 1′,2′ ) 6.6 Hz), 8.50 (s, 1 H, H-2 or H-8), 8.76 (s, 1 H,
H-2 or H-8). Anal. (C12H17N7O4‚2HCl) C, H, N.
CH2 × 4), 4.00 (m, 1 H, CHNH), 4.14 (dd, 1 H, H-3′, J 3′,2′
)
4.6, J 3′,4′ ) 1.9 Hz), 4.34 (d, 1 H, H-4′, J 4′,3′ ) 1.9 Hz), 4.57 (dd,
1 H, H-2′, J 2′,1′ ) 6.6, J 2′,3′ ) 4.6 Hz), 5.98 (d, 1H, H-1′, J 1′,2′
)
6.6 Hz), 8.32 (s, 1H, H-2 or H-8), 8.68 (s, 1H, H-2 or H-8). Anal.
(C15H20N6O4) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-cycloh exyl-â-D-r ib ofu r a n -
u r on a m id e (27): yield 197 mg (54%, white foam); FAB-MS
m/z 363 (MH+); 1H NMR (DMSO-d6 + D2O) 1.15-1.81 (m, 10
H, CH2 × 5), 3.62 (m, 1 H, CHNH), 4.09 (dd, 1 H, H-3′, J 3′,2′
)
4.6, J 3′,4′ ) 1.3 Hz), 4.29 (d, 1 H, H-4′, J 4′,3′ ) 1.3 Hz), 4.60 (dd,
1 H, H-2′, J 2′,1′ ) 7.3, J 2′,3′ ) 4.6 Hz), 5.93 (d, 1 H, H-1′, J 1′,2′
)
7.3 Hz), 8.37 (s, 1 H, H-2 or H-8), 8.47 (s, 1 H, H-2 or H-8).
Anal. (C16H22N6O4‚1/4H2O) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-cycloh ep t yl-â-D-r ib ofu r a n -
u r on a m id e (28): yield 333 mg (89%, colorless foam); FAB-
MS m/z 377 (MH+); 1H NMR (DMSO-d6 + D2O) 1.38-1.81 (m,
12 H, CH2 × 6), 3.79 (m, 1 H, CHNH), 4.09 (d, 1 H, H-3′, J 3′,2′
) 4.3 Hz), 4.28 (s, 1 H, H-4′), 4.59 (dd, 1 H, H-2′, J 2′,1′ ) 7.6,
J 2′,3′ ) 4.3 Hz), 5.92 (d, 1 H, H-1′, J 1′,2′ ) 7.6 Hz), 8.15 (s, 1 H,
H-2 or H-8), 8.37 (s, 1 H, H-2 or H-8). Anal. (C17H24N6O4) C,
H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-cyclooct yl-â-D-r ib ofu r a n -
u r on a m id e (29): yield 328 mg (84%, white foam); FAB-MS
m/z 391 (MH+); 1H NMR (DMSO-d6 + D2O) 1.45-1.72 (m, 14
H, CH2 × 7), 3.84 (m, 1 H, CHNH), 4.09 (d, 1 H, H-3′, J 3′,2′
)
4.6 Hz), 4.28 (s, 1 H, H-4′), 4.58 (dd, 1 H, H-2′, J 2′,1′ ) 7.5, J 2′,3′
) 4.6 Hz), 5.92 (d, 1 H, H-1′, J 1′,2′ ) 7.5 Hz), 8.38 (s, 1 H, H-2
or H-8), 8.45 (s, 1 H, H-2 or H-8). Anal. (C18H26N6O4) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-(4-m eth ylcycloh exyl)-â-D-r i-
bofu r a n u r on a m id es (30, 31): yield 371 mg (98%, white
solid). This material contained both cis- and trans-isomers
(ratio 37:63, respectively), which were separated by C-18
HPLC (YMC-D-ODS-5) with 50% aqueous MeOH at a flow rate
of 10 mL/min to give 30 (retention time 37 min, white solid)
and 31 (retention time 54 min, white solid).
1-(Ad en in -9-yl)-1-d eoxy-N-a m in ooct yl-â-D-r ib ofu r a n -
u r on a m id e d ih yd r och lor id e (21): yield 401 mg (82%, white
solid); FAB-MS m/z 408 (MH+); 1H NMR (DMSO-d6 + D2O)
1.41 (m, 12 H, CH2 × 6), 2.29 (t, 2 H, CH2NH, J ) 6.6 Hz),
2.70 (t, 2 H, CH2NH, J ) 7.2 Hz), 4.15 (d, 1 H, H-3′, J 3′,2′ ) 4.6
Hz), 4.36 (s, 1 H, H-4′), 4.56 (dd, 1 H, H-2′, J 2′,1′ ) 6.6, J 2′,3′
)
4.6 Hz), 6.02 (d, 1 H, H-1′, J 1′,2′ ) 6.6 Hz), 8.45 (s, 1 H, H-2 or
H-8), 8.77 (s, 1 H, H-2 or H-8). Anal. (C18H29N7O4‚2HCl‚1/2H2O)
C, H, N. Ref 22 describes the synthesis of a free amine of 21.
1-(Aden in -9-yl)-1-deoxy-N-acetam idoeth yl-â-D-r ibofu r a-
n u r on a m id e (22): yield 323 mg (88%, white solid); FAB-MS
m/z 366 (MH+); 1H NMR (DMSO-d6 + D2O) 1.71 (s, 3 H, CH3),
3.10 (m, 4 H, CH2 × 2), 4.13 (d, 1 H, H-3′, J 3′,2′ ) 4.6 Hz), 4.28
(s, 1 H, H-4′), 4.57 (dd, 1 H, H-2′, J 2′,1′ ) 7.9, J 2′,3′ ) 4.6 Hz),
5.92 (d, 1 H, H-1′, J 1′,2′ ) 7.9 Hz), 8.22 (s, 1 H, H-2 or H-8),
8.32 (s, 1 H, H-2 or H-8). Anal. (C14H19N7O5‚1/5H2O) C, H, N.
1-(Aden in -9-yl)-1-deoxy-N-acetam idooctyl-â-D-r ibofu r a-
n u r on a m id e (23): yield 132 mg (29%, white foam); FAB-MS
m/z 450 (MH+); 1H NMR (DMSO-d6 + D2O) 1.19 (m, 12 H, CH2
× 6), 1.73 (s, 3 H, Ac), 2.94 (t, 2 H, CH2NH, J ) 6.6 Hz), 3.16
(t, 2 H, CH2NH, J ) 7.2 Hz), 4.08 (d, 1 H, H-3′, J 3′,2′ ) 4.6 Hz),
4.29 (s, 1 H, H-4′), 4.57 (dd, 1 H, H-2′, J 2′,1′ ) 7.9, J 2′,3′ ) 4.6
Hz), 5.92 (d, 1 H, H-1′, J 1′,2′ ) 7.9 Hz), 8.15 (s, 1 H, H-2 or
H-8), 8.34 (s, 1 H, H-2 or H-8). Anal. (C20H31N7O5‚1/5H2O) C,
H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-(cis-4-m eth ylcycloh exyl)-â-
D-r ibofu r a n u r on a m id e (30): FAB-MS m/z 377 (MH+); 1H
NMR (DMSO-d6 + D2O) 0.85 (d, 3 H, CH3, J ) 6.6 Hz), 1.17-
1.56 (m, 9 H, CH2 × 4, CH), 3.75 (m, 1 H, CHNH), 4.13 (dd, 1
H, H-3′, J 3′,2′ ) 4.6, J 3′,4′ ) 1.9 Hz), 4.35 (d, 1 H, H-4′, J 4′,3′
)
1.9 Hz), 4.62 (dd, 1 H, H-2′, J 2′,1′ ) 7.3, J 2′,3′ ) 4.6 Hz), 5.94 (d,
1 H, H-1′, J 1′,2′ ) 7.3 Hz), 8.12 (s, 1 H, H-2 or H-8), 8.43 (s, 1
H, H-2 or H-8). Anal. (C17H24N6O4‚1/5H2O) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-(tr a n s-4-m eth ylcycloh exyl)-
â-D-r ibofu r a n u r on a m id e (31): FAB-MS m/z 377 (MH+); 1H
NMR (DMSO-d6 + D2O) 0.85 (d, 3 H, CH3, J ) 6.6 Hz), 0.93-
1.83 (m, 9 H, CH2 × 4, CH), 3.50 (m, 1H, CHNH), 4.08 (dd, 1
H, H-3′, J 3′,2′ ) 4.6, J 3′,4′ ) 1.3 Hz), 4.27 (d, 1 H, H-4′, J 4′,3′
)
1.3 Hz), 4.58 (dd, 1 H, H-2′, J 2′,1′ ) 7.9, J 2′,3′ ) 4.6 Hz), 5.92 (d,
1 H, H-1′, J 1′,2′ ) 7.9 Hz), 8.15 (s, 1 H, H-2 or H-8), 8.36 (s, 1
H, H-2 or H-8). Anal. (C17H24N6O4‚1/2H2O) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-(2-m eth ylcycloh exyl)-â-D-r i-
bofu r a n u r on a m id e (32): yield 365 mg (95%, white foam,
mixture of four diastereomers, ratio ) 2:2:3:3); FAB-MS m/z
377 (MH+); 1H NMR (DMSO-d6 + D2O) 0.70-0.85 (m, 3 H,
CH3), 0.99-1.75 (m, 9 H, CH2 × 4, CH), 3.27-3.40 (m, 0.7 H,
CHNH), 3.86-3.91 (m, 0.3 H, CHNH), 4.11 (m, 1 H, H-3′), 4.31
(d, 0.3 H, H-4′, J 4′,3′ ) 1.4 Hz), 4.32 (d, 0.3 H, H-4′, J 4′,3′ ) 1.4
Hz), 4.41 (d, 0.2 H, H-4′, J 4′,3′ ) 2.4 Hz), 4.45 (d, 0.2 H, H-4′,
J 4′,3′ ) 2.2 Hz), 4.54-4.63 (m, 1 H, H-2′), 5.92-5.98 (m, 1 H,
H-1′), 8.17 (s, 0.3 H, H of 2 or 8), 8.19 (br s, 0.7 H, H of 2 or 8),
8.39 (s, 0.3 H, H of 2 or 8), 8.45 (s, 0.3 H, H of 2 or 8), 8.50 (s,
0.2 H, H of 2 or 8), 8.55 (s, 0.2 H, H of 2 or 8). Anal.
(C17H24N6O4‚1/3H2O) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-(exo-n or bor n a n -2-yl)-â-D-r i-
bofu r a n u r on a m id e (33): yield 365 mg (95%, mixture of two
diastereomers, ratio ) 1:1); mp 159-161 °C (crystallized from
aqueous MeOH); FAB-MS m/z 375 (MH+); 1H NMR (270 MHz,
DMSO-d6 + D2O) 1.07-1.65 (m, 8 H, CH2 × 4), 2.03 (s, 0.5 H,
CH), 2.14 (s, 0.5 H, CH), 2.25 (br s, 1 H, CH), 3.54 (br s, 0.5 H,
CHNH), 3.62 (br s, 0.5 H, CHNH), 4.08 (m, 1 H, H-3′), 4.28 (s,
1-(Ad en in -9-yl)-1-d eoxy-N-cyclop r op yl-â-D-r ibofu r a n -
u r on a m id e (24): yield 253 mg (79%); mp 249-251 °C
(crystallized from 2-propanol-hexane) (lit.20 mp 249-250 °C);
1
EI-MS m/z 320 (M+); H NMR (DMSO-d6 + D2O) 0.39-0.53
(m, 2 H, CH2), 0.62-0.76 (m, 2 H, CH2), 2.70 (m, 1 H, CHNH),
4.11 (dd, 1 H, H-3′, J 3′,2′ ) 4.6, J 3′,4′ )1.3 Hz), 4.26 (d, 1 H,
H-4′, J 4′,3′ ) 1.3 Hz), 4.55 (dd, 1 H, H-2′, J 2′,1′ ) 7.3, J 2′,3′ ) 4.6
Hz), 5.92 (d, 1 H, H-1′, J 1′,2′ ) 7.3 Hz), 8.13 (s, 1 H, H-2 or
H-8), 8.37 (s, 1 H, H-2 or H-8). Anal. (C13H16N6O4) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-cyclob u t yl-â-D-r ib ofu r a n -
u r on a m id e (25): yield 303 mg (91%); mp 235 °C (crystallized
from aqueous EtOH) (lit.20 mp 234-235 °C); FAB-MS m/z 335
1
(MH+); H NMR (DMSO-d6 + D2O) 1.59-1.75 (m, 2 H, CH2),
1.83-2.07 (m, 2 H, CH2), 2.13-2.29 (m, 2 H, CH2), 4.09 (dd, 1
H, H-3′, J 3′,2′ ) 4.6, J 3′,4′ )1.3 Hz), 4.21-4.36 (m, 2 H, H-4′,
CHNH), 4.59 (dd, 1H, H-2′, J 2′,1′ ) 7.3, J 2′,3′ ) 4.6 Hz), 5.93 (d,
1H, H-1′, J 1′,2′ ) 7.3 Hz), 8.18 (s, 1H, H-2 or H-8), 8.37 (s, 1H,
H-2 or H-8). Anal. (C14H18N6O4) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-cyclop en t yl-â-D-r ib ofu r a n -

5′-N-Ethylcarboxamidoadenosine Derivatives
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 2 213
solid); FAB-MS m/z 447 (MH+); 1H NMR (DMSO-d6 + D2O)
1 H, H-4′), 4.58 (m, 1 H, H-2′), 5.92 (m, 1 H, H-1′), 8.08 (s, 1
H, H-2 or H-8), 8.37 (s, 0.5 H, H-2 or H-8), 8.38 (s, 0.5 H, H-2
or H-8). Anal. (C17H22N6O4‚1/5H2O) C, H, N.
3.69 (s, 6 H, CH3O × 2), 4.16 (dd, 1 H, H-3′, J 3′,2′ ) 4.6, J 3′,4′
)
1.3 Hz), 4.29 (d, 1 H, H-4′, J 4′,3′ ) 1.3 Hz), 4.45 (dd, 1 H, H-2′,
J 2′,1′ ) 7.3, J 2′,3′ ) 4.6 Hz), 4.76 (d, 2 H, CH2, J ) 4.0 Hz), 5.92
(d, 1 H, H-1′, J 1′,2′ ) 7.3 Hz), 6.85-6.99 (m, 3 H, o,m, -Ph),
7.96 (s, 1 H, H-2 or H-8), 8.35 (s, 1 H, H-2 or H-8). Anal.
(C19H22N6O7‚1/5H2O) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-(a d a m a n t a n -1-yl)-â-D-r ib o-
fu r a n u r on a m id e (34): yield 386 mg (92%); mp 201-202 °C
(crystallized from MeOH); FAB-MS m/z 415 (MH+); H NMR
1
(DMSO-d6 + D2O) 1.61 (br s, 6 H, CH2 × 3), 1.94 (br s, 6 H,
CH2 × 3), 2.01 (br s, 3 H, CH × 3), 4.09 (dd, 1 H, H-3′, J 3′,2′
)
Ack n ow led gm en t . This investigation was sup-
ported in part by a grant from the Ministry of Educa-
tion, Science, Sports, and Culture of J apan.
4.8, J 3′,4′ ) 1.3 Hz), 4.21 (d, 1 H, H-4′, J 4′,3′ ) 1.3 Hz), 4.66 (dd,
1 H, H-2′, J 2′,1′ ) 7.4, J 2′,3′ ) 4.8 Hz), 5.91 (d, 1 H, H-1′, J 1′,2′
)
7.4 Hz), 8.13 (s, 1 H, H-2 or H-8), 8.39 (s, 1 H, H-2 or H-8).
Anal. (C20H26N6O4‚1/3H2O) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-(a d a m a n t a n -2-yl)-â-D-r ib o-
fu r a n u r on a m id e (35): yield 249 mg (60%); mp 158-159 °C
Su p p or tin g In for m a tion Ava ila ble: Elemental analyses
for compounds 10-42. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
(crystallized from MeOH); FAB-MS m/z 415 (MH+); H NMR
(DMSO-d6 + D2O) 1.43-1.48 (m, 2 H, CH2), 1.65-1.88 (m, 12
H, CH2 × 4, CH × 4), 3.86 (m, 1 H, CHNH), 4.15 (dd, 1 H,
H-3′, J 3′,2′ ) 4.6, J 3′,4′ ) 2.1 Hz), 4.43 (d, 1 H, H-4′, J 4′,3′ ) 2.1
Hz), 4.68 (dd, 1 H, H-2′, J 2′,1′ ) 6.9, J 2′,3′ ) 4.6 Hz), 5.95 (d, 1
H, H-1′, J 1′,2′ ) 6.9 Hz), 8.07 (s, 1 H, H-2 or H-8), 8.45 (s, 1 H,
H-2 or H-8). Anal. (C20H26N6O4‚1/10H2O) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-(n or a d a m a n ta n -3-yl)-â-D-r i-
bofu r a n u r on a m id e (36): yield 64 mg (16%, white solid);
FAB-MS m/z 401 (MH+); 1H NMR (DMSO-d6 + D2O) 1.47-
1.56 (m, 4 H, CH2 × 2), 1.83-2.04 (m, 6 H, CH2 × 3), 2.20 (br
s, 2 H, CH × 2), 2.36 (t, 1 H, CH, J ) 6.5 Hz), 4.11 (d, 1 H,
H-3′, J 3′,2′ ) 4.7 Hz), 4.27 (s, 1 H, H-4′), 4.64 (dd, 1 H, H-2′,
J 2′,1′ ) 7.3, J 2′,3′ ) 4.7 Hz), 5.92 (d, 1 H, H-1′, J 1′,2′ ) 7.3 Hz),
8.12 (s, 1 H, H-2 or H-8), 8.37 (s, 1 H, H-2 or H-8). Anal.
(C19H24N6O4‚1/5H2O) C, H, N.
Refer en ces
(1) Part 199: Kodama, T.; Shuto, S.; Nomura, M.; Matsuda, A.
Synthesis of a 1′R-phenylselenouridine derivative as a synthetic
precursor for various 1′-modified nucleosides, via enolization at
the 1′-position of 3′,5′-O-TIPDS-2′-ketouridine. Tetrahedron Lett.
2000, 41, 3643-3646.
(2) Olah, M. E.; Stiles, G. L. Adenosine receptor subtypes: charac-
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1-(Aden in -9-yl)-1-deoxy-N-h ydr oxy-â-D-r ibofu r an u r on a-
m id e (37): yield 178 mg (58%, white solid); FAB-MS m/z 297
1
(MH+); H NMR (270 MHz, DMSO-d6 + D2O) 4.15 (dd, 1 H,
H-3′, J 3′,2′ ) 4.6, J 3′,4′ ) 2.6 Hz), 4.27 (d, 1 H, H-4′, J 4′,3′ ) 2.6
Hz), 4.51 (dd, 1 H, H-2′, J 2′,1′ ) 6.6, J 2′,3′ ) 4.6 Hz), 5.94 (d, 1
H, H-1′, J 1′,2′ ) 6.6 Hz), 8.15 (s, 1 H, H-2 or H-8), 8.44 (s, 1 H,
H-2 or H-8). Anal. (C10H12N6O5‚1/2H2O) C, H, N.
1-(Aden in -9-yl)-1-deoxy-N-m eth oxy-â-D-r ibofu r an u r on a-
m id e (38): yield 195 mg (63%, white solid) (lit.20 mp 113 °C,
dec, lit.23 mp 125 °C); FAB-MS m/z 311 (MH+); 1H NMR
(DMSO-d6 + D2O) 3.64 (s, 3 H, CH3), 4.21 (dd, 1 H, H-3′, J 3′,2′
) 4.6, J 3′,4′ ) 2.0 Hz), 4.28 (d, 1 H, H-4′, J 4′,3′ ) 2.0 Hz), 4.54
(dd, 1 H, H-2′, J 2′,1′ ) 7.2, J 2′,3′ ) 4.6 Hz), 5.95 (d, 1 H, H-1′,
J 1′,2′ ) 7.2 Hz), 8.16 (s, 1 H, H-2 or H-8), 8.38 (s, 1 H, H-2 or
H-8). Anal. (C11H14N6O5‚4/5H2O) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-eth oxy-â-D-r ibofu r a n u r on a -
m id e (39): yield 204 mg (63%); mp 159-161 °C (crystallized
from EtOH-hexane); FAB-MS m/z 325 (MH+); 1H NMR
(DMSO-d6 + D2O) 1.96 (t, 3 H, CH3, J ) 7.3 Hz), 3.85 (q, 2 H,
CH2CH3, J ) 7.3 Hz), 4.19 (dd, 1 H, H-3′, J 3′,2′ ) 4.6, J 3′,4′
)
2.0 Hz), 4.29 (d, 1 H, H-4′, J 4′,3′ ) 2.0 Hz), 4.53 (dd, 1 H, H-2′,
J 2′,1′ ) 7.2, J 2′,3′ ) 4.6 Hz), 5.95 (d, 1 H, H-1′, J 1′,2′ ) 7.2 Hz),
8.15 (s, 1 H, H-2 or H-8), 8.37 (s, 1 H, H-2 or H-8). Anal.
(C12H16N6O5) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-isob u t yloxy-â-D-r ibofu r a n -
u r on a m id e (40): yield 357 mg (99%); mp 147-150 °C
(crystallized from aqueous MeOH); FAB-MS m/z 353 (MH+);
1H NMR (DMSO-d6 + D2O) 0.88 (d, 6 H, CH3 × 2, J ) 6.6
Hz), 1.86 (m, 1 H, CH), 3.59 (d, 2 H, CH2, J ) 6.6 Hz), 4.19
(dd, 1 H, H-3′, J 3′,2′ ) 4.6, J 3′,4′ ) 2.0 Hz), 4.28 (d, 1 H, H-4′,
J 4′,3′ ) 2.0 Hz), 4.53 (dd, 1 H, H-2′, J 2′,1′ ) 7.2, J 2′,3′ ) 4.6 Hz),
5.95 (d, 1 H, H-1′, J 1′,2′ ) 7.2 Hz), 8.14 (s, 1 H, H-2 or H-8),
8.39 (s, 1 H, H-2 or H-8). Anal. (C14H20N6O5‚1/2H2O) C, H, N.
1-(Ad en in -9-yl)-1-d eoxy-N-b en zyloxy-â-D-r ib ofu r a n -
u r on a m id e (41): yield 309 mg (78%); mp 131-134 °C
1
(crystallized from aqueous MeOH); EI-MS m/z 386 (M+); H
NMR (DMSO-d6 + D2O) 4.18 (dd, 1 H, H-3′, J 3′,2′ ) 4.6, J 3′,4′
)
2.0 Hz), 4.30 (d, 1 H, H-4′, J 4′,3′ ) 2.0 Hz), 4.48 (dd, 1 H, H-2′,
J 2′,1′ ) 6.6, J 2′,3′ ) 4.6 Hz), 4.85 (s, 2 H, CH2), 5.94 (d, 1 H,
H-1′, J 1′,2′ ) 6.6 Hz), 7.31-7.43 (m, 5 H, o,m,p-Ph), 8.04 (s, 1
H, H-2 or H-8), 8.42 (s, 1 H, H-2 or H-8). Anal. (C17H18N6O5‚
1/2H2O) C, H, N.
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1-(Ad en in -9-yl)-1-d eoxy-N-(3,4,-d im eth oxyben zyloxy)-
â-D-r ibofu r a n u r on a m id e (42): yield 77 mg (17%, white

214 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 2
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