AMP deaminase inhibitors. 3. SAR of 3-(carboxyarylalkyl)coformycin aglycon analogues

Article abstract of DOI:10.1021/jm990448e

N3-Substituted coformycin aglycon analogues with improved AMP deaminase (AMPDA) inhibitory potency are described. Replacement of the 5-carboxypentyl substituent in the lead AMPDA inhibitor 3-(5-carboxypentyl)-3,6,7,8- tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (2) described in the previous article with various carboxyarylalkyl groups resulted in compounds with 10- 100-fold improved AMPDA inhibitory potencies. The optimal N3 substituent had m-carboxyphenyl with a two-carbon alkyl tether. For example, 3-[2-(3-carboxy- 5-ethylphenyl)ethyl]-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (43g) inhibited human AMPDA with a K(i) = 0.06 μM. The compounds within the series also exhibited > 1000-fold specificity for AMPDA relative to adenosine deaminase.

Full text of DOI:10.1021/jm990448e

1508
J . Med. Chem. 2000, 43, 1508-1518
AMP Dea m in a se In h ibitor s. 3. SAR of 3-(Ca r boxya r yla lk yl)cofor m ycin Aglycon
An a logu es
Srinivas Rao Kasibhatla,* Brett C. Bookser, Gary Probst, J ames R. Appleman, and Mark D. Erion
Metabasis Therapeutics Inc., 9390 Towne Centre Drive, San Diego, California 92121
Received August 31, 1999
N3-Substituted coformycin aglycon analogues with improved AMP deaminase (AMPDA)
inhibitory potency are described. Replacement of the 5-carboxypentyl substituent in the lead
AMPDA inhibitor 3-(5-carboxypentyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (2)
described in the previous article with various carboxyarylalkyl groups resulted in compounds
with 10-100-fold improved AMPDA inhibitory potencies. The optimal N3 substituent had
m-carboxyphenyl with a two-carbon alkyl tether. For example, 3-[2-(3-carboxy-5-ethylphenyl)-
ethyl]-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (43g) inhibited human AMPDA with
a Ki ) 0.06 µM. The compounds within the series also exhibited >1000-fold specificity for
AMPDA relative to adenosine deaminase.
Ch a r t 1
In tr od u ction
AMP deaminase (AMPDA) represents a potential
target for novel antiischemic drug therapy based on its
putative role in adenosine production.1 In the initial
communication of our effort to discover AMPDA inhibi-
tors, we described the design of potent, specific, and cell-
penetrable AMPDA inhibitors using a transition-state
(TS) mimicry strategy.2,3 As described in the preceding
article, the initial set of compounds in this series
supported this design concept. This work demonstrated
that replacement of the phosphorylated sugar of the
potent TS inhibitor coformycin monophosphate (1) with
a simple carboxyalkyl group resulted in retention of
significant AMPDA inhibitory potency. Structure-
activity studies showed that AMPDA inhibition was
dependent on the terminal carboxylic acid and length
of the alkyl group. The lead compound in the series was
compound 2 wherein the N3 substituent was 5-carboxy-
pentyl.
Sch em e 1a
2
5
3
4
6
a
Reagents: (a) NaH, DMF; NaI; (b) NaBH4, MeOH, CH2Cl2;
(c) 1 N NaOH, dioxane.
Ch em istr y
The AMPDA inhibitor analogues (Tables 1 and 2)
were prepared using the general three-step procedure
outlined in Scheme 1. Alkylation of the heterocycle 6,7-
dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one (3)4 with
an appropriate electrophile in the presence of NaH gave
the desired N3 regioisomer as the major product.5
Reduction of the alkylation products with NaBH4 fur-
nished the corresponding racemic alcohols 5. Saponifi-
cation of the esters with aqueous NaOH in dioxane
provided the desired carboxylic acids 6.
To improve the potency of 2, we focused on replacing
the flexible N3 side chain with a more structurally rigid
surrogate. One possibility was the incorporation of an
aryl group between the alkyl moiety and the carboxylate
(Chart 1). Herein we report the optimization of the
tether length (X) and the position of the carboxylic acid
and how this investigation resulted in generating potent
and selective AMPDA inhibitors.
Electr op h ile P r ep a r a tion . Many of the electro-
philes were constructed using palladium-catalyzed cou-
pling reactions. The electrophiles 11 and 12 were
prepared from a common intermediate 9, which was
* To whom correspondence should be addressed. Phone: 858-622-
5514. Fax: 858-622-5526. E-mail: rao@mbasis.com.
10.1021/jm990448e CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/25/2000

AMP Deaminase Inhibitors. 3
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8 1509
Sch em e 2a
isomers 21a and 22. Deprotection of isomer 21a followed
by bromination gave the electrophile 23 (Scheme 5).
Similarly, the 5-substituted regioisomer benzyl 5-(2-
bromoethyl)-2-thiophenecarboxylate was made from
2-(2-thienyl)ethanol. Finally, a method similar to that
described in Scheme 3 was used for the preparation of
three-carbon-tethered heteroaromatic ring electrophiles.
The electrophiles methyl 3-(3-bromopropyl)-1-thiophen-
ecarboxylate and methyl 5-(3-bromopropyl)-1-furancar-
boxylate were prepared from the corresponding starting
materials methyl 3-bromo-1-thiophenecarboxylate and
methyl 5-bromo-1-furancarboxylate, respectively.
a
Reagents: (a) H2SO4, EtOH; (b) vinyltributyltin, Pd(PPh3)4,
The electrophiles 27a -g, 34a ,b, and 39a -c were used
to prepare analogues with a m-carboxyphenethyl as the
N3 substituent. Two different routes were used for their
preparation. In some cases, oxidative cleavage of allyl-
phenyl derivatives (Schemes 6 and 7) was used, while
in other cases, oxidation of the styryl derivatives was a
key step (Scheme 8). Schemes 6 and 7 outline the
synthesis of the substituted allylphenyl compounds via
palladium-catalyzed coupling reaction and Claisen rear-
rangement, respectively. Treatment of the allyl deriva-
tive, e.g. 25a , with O3 followed by in situ reduction of
the ozonide with NaBH4 gave the alcohol derivative 26a ,
which upon bromination yielded the electrophile 27a .
In the case of compound 25e, the oxidation was per-
formed using NaIO4 in the presence of RuO2. The
TBDMS-protected derivative 27b was obtained by a
similar sequence from 24b, which was prepared by
halogenation of 24a with NBS followed by hydroxide
displacement and TBDMS protection. The electrophile
27g was synthesized from the intermediate 26e.
DMF; (c) i. NaIO4, OsO4, NMO, t-BuOH, THF; NaHCO3, ii. NaBH4,
MeOH; (d) CBr4, PPh3, CH2Cl2; (e) 9-BBN, THF; 30% H2O2, 3 N
NaOH.
readily prepared from 8 (Scheme 2).6a Oxidative cleav-
age of 9 with NaIO4 in the presence of osmium tetroxide
followed by NaBH4 reduction and bromination gave the
benzyl bromide derivative 11. Similarly, hydroboration/
oxidation of 9 followed by bromination provided the
phenethyl derivative 12.
Compounds with a three-carbon tether, 16a -i and 17,
were prepared using the sequence depicted in Scheme
3. Intermediates 15a -i were prepared from the corre-
sponding phenols 13a -e and aryl iodides 14f-i using
a palladium coupling reaction.6b Propargyl alcohols
15a -i were hydrogenated and converted to bromides
16a -i. Propargyl bromide derivative 17 was made from
the corresponding alcohol 15g.
Electrophiles containing a heteroatom in the linker
were prepared by the route described in Scheme 4.
Mitsunobu reaction or base alkylation of phenols/
thiophenols 18a -c,f provided the corresponding alky-
lation products 19a -d . Compound 18f was prepared by
carboxylation of thiol7 18d followed by esterification.
Heteroaromatic rings were introduced in the side
chain using two different approaches. Reaction of TB-
DMS-protected 2-(3-thienyl)ethanol 20b with n-BuLi
followed by methyl chloroformate gave the two regio-
The electrophiles 34a ,b were prepared in a five-step
sequence (Scheme 7). Alkylation of the methyl 4-hy-
droxybenzoate (28) with allyl bromide followed by
Claisen rearrangement in the presence of the Lewis acid
BCl3 in chlorobenzene gave the allyl derivative 29.
Treatment of 29 with O3 and subsequent reduction of
the ozonide with NaBH4 and protection of the resultant
hydroxyl group with TBDMSCl provided the intermedi-
Sch em e 3a
a
Reagents: (a) i. H2SO4, MeOH, ii. Tf2O, Et3N, THF, iii. propargyl alcohol, Pd(PPh3)2Cl2, Et2NH, DMF; (b) i. H2SO4, MeOH, ii. propargyl
alcohol, Pd(PPh3)2Cl2, Et2NH, CuI, DMF; (c) 10% Pd/C, H2, EtOAc; (d) CBr4, PPh3, CH2Cl2.

1510 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8
Kasibhatla et al.
Sch em e 4a
verted to their corresponding bromides 39a -c by hy-
droboration/oxidation followed by bromination.
Some modifications on the side chain aromatic ring
were also introduced at a later stage of the synthesis
as shown in Scheme 9. Suzuki cross-coupling of the
compound 40a with substituted phenylboronic acids in
the presence of a base provided the biphenyl derivatives
41a -d .6d Desilylation of 40b delivered compound 41e.
Resu lts
The compounds described above (Tables 1 and 2) were
evaluated as inhibitors of porcine heart AMPDA and
calf intestinal ADA, and the results are reported in
Tables 3-6.8 The inhibitor initial screening concentra-
tions in general were chosen so that the upper limits of
the Ki values determined for AMPDA and ADA inhibi-
tion were 125 and 7.5 µM, respectively. In select
examples, to evaluate the full extent of the selectivity
of the enzyme inhibition, ADA inhibition was evaluated
at higher concentrations.
a
Reagents: (a) n-BuLi, cyclohexane, TMEDA, CO2; (b) MeOH,
H2SO4; (c) Br(CH2)2Br, K2CO3, DMSO; (d) Br(CH2)2OH, PPh3,
DEAD, THF.
Sch em e 5a
Compounds listed in Table 3 explored the dependence
of the AMPDA inhibition activity on the distance
between N3 and the carboxylic acid group, which in the
initial AMPDA inhibitor series was determined to be
5-6 atoms.3 As indicated in Table 3 a two-atom tether
length and a carboxylic acid group in a meta position
exhibited a 9-fold improvement over the lead compound
2 (e.g. 42s, AMPDA Ki ) 0.5 µM). In contrast, a
carboxylic acid group at the ortho or para position on
the phenyl ring with varied alkyl tether lengths resulted
in decreased or no significant enhancement in activity.
Similarly, a carboxylic acid group in the meta position
with a tether length of three atoms showed no improve-
ment over 2.
To further optimize the series we explored the effect
of various phenyl ring substituents on the AMPDA
inhibitory potency of 42s. The results shown in Table 4
indicated that analogues with small substituents such
as methyl at the C6 (e.g. 43a , AMPDA Ki ) 0.1 µM) or
analogues with an ethyl at the C5 (e.g. 43g, AMPDA Ki
) 0.06 µM) exhibited a 5- and 9-fold increase in potency,
respectively, with maintained selectivity. To delineate
the effects of size, shape, and polarity of the phenyl
substituents on affinity to the enzyme, we examined
various substituents at the C5 and C6. Substituents
such as bromine (43h ) and phenyl (43i) at the C5 were
well-tolerated. Polar substituents such as methoxy,
hydroxymethyl, or halogen, such as F, at the C6 of the
a
Reagents: (a) TBDMSCl, imidazole, DMF; (b) n-BuLi, THF,
ClCO2CH3; (c) TBAF, THF; (d) CBr4, PPh3, CH2Cl2.
ate 30. The palladium-catalyzed coupling of the triflate
of 30 with vinyltributylstannane and allyltributylstan-
nane followed by hydrogenation provided the respective
ethyl and propyl derivatives of 32a ,b. Desilylation with
CSA in methanol followed by bromination gave the
compounds 34a ,b.
The synthesis of the compounds 39a -c from the
intermediate m-carboxyalkylstyryl derivatives 37a -c
followed the route indicated in Scheme 8. Carbometh-
oxylation6c of compounds 35a ,b with CO in the presence
of Pd(0) in MeOH followed by Wittig olefination with
triphenylphosphinemethyl bromide and n-BuLi pro-
vided the styryl derivatives 37a ,b, whereas 37c was
prepared from 36 by palladium-catalyzed vinylation.
These vinyl intermediate derivatives 37a -c were con-
Sch em e 6a
a
Reagents: (a) i. NBS, benzoyl peroxide, CCl4, ii. CaCO3, H2O, dioxane, iii. TBDMSCl, imidazole, DMF; (b) allyltributyltin, Pd(PPh3)4,
DMF; (c) O3, MeOH; NaBH4; (d) NaIO4, RuO2, CCl4, CH3CN; NaBH4, MeOH (when R5 ) Br); (e) vinyltributyltin, Pd(PPh3)4, DMF; (f)
10% Pd/C, H2, EtOAc; (g) CBr4, PPh3, CH2Cl2.

AMP Deaminase Inhibitors. 3
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8 1511
Ta ble 1. Physical Data and Methods of Preparation of AMPDA Inhibitors (Acids)
compd
mp (°C)
ndb
122-125
204
starting material; methods
formulaa
anal.
42a
42b
42c
42d
42e
42f
42g
42h
42i
14e; D, L, N, W, X, Y
13a ; A, C, L, N, W, X, Y
13b; A, C, L, N, W, X, Y
14f; A, D, L, N, W, X, Y
13c; A, C, L, N, W, X, Y
13d ; A, C, L, N, W, X, Y
18a ; A, F, W, X, Y
C16H17N4O3Na‚0.25H2O
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
LRMS
LRMS
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C
C
C
17H20N4O3‚1.1H2O‚0.1AcOH
17H20N4O3‚1.5H2O
205
16H17N4O3F‚1.4H2O
C19H24N4O3‚0.6H2O
210c
ndb
C20H20N4O3‚1.1H2O‚0.4AcOH
C15H15N4O4Na‚3.5H2O
ndb
200
18c; A, F, W, X, Y
C15H16N4O3S‚0.1AcOH
ndb
18d ; E, A, F, W, X, Y
commercially available
commercially available
7; A, J , P, N, W, X, Y
7; A, J , B, N, W, X, Y
18b; A, G, W, X, Y
14g; D, L, N, W, X, Y
14h ; A, D, L, N, W, X, Y
14i; D, L, N, W, X, Y
14g; D, N, W, X, Y
24f; J , M, N, W, X, Y
24a ; J , M, N, W, X, Y
24c; J , M, N, W, X, Y
24d ; J , M, N, W, X, Y
24a ; I, J , M, N, W, X, Y
28; Q, M, R, S, L, T, N, W, X, Y
28; Q, M, R, S, L, T, N, W, X, Y
24e; J , K, J , L, N, W, X, Y
24e; J , K, N, W, X, Y
24e; J , K, N, W, X, U, Y
24e; J , K, N, W, X, U, Y
24e; J , K, N, W, X, U, Y
24e; J , K, N, W, X, U, Y
35b; O, H, P, N, W, X, Y
35a ; O, H, P, N, W, X, Y
36; J , P, N, W, X, Y
C18H22N4O3S‚2.0H2O
C14H13N4O3Na‚2.5H2O
C15H15N4O3Na‚2.5H2O
C15H15N4O3Na‚2.0H2O
C15H16N4O3‚0.8H2O
42j
42k
42l
ndb
ndb
ndb
42m
42n
42o
42p
42q
42r
42s
43a
43b
43c
43d
43e
43f
43g
43h
43i
206-208c
210c
C15H15N4O4Na‚1.0H2O
C16H17N4O3Na‚0.25H2O
C17H19N4O3Na‚2.0H2O
C17H20N4O4‚0.25H2O
C16H13N4O3Na‚1.0H2O
C15H16N4O3‚1.1H2O
204-206c
ndb
ndb
224-226c
210c
142-145
184-186
235c
C
C
16H18N4O3‚2.0H2O‚0.1AcOH
16H18N4O4‚0.5H2O‚0.2AcOH
C15H15N4O3F‚2.1H2O‚0.1AcOH
C16H18N4O4‚1.5H2O‚0.5AcOH
C17H20N4O3‚2.7H2Od
C18H22N4O3‚3.4H2O‚0.2AcOH
C17H20N4O3‚2.0H2O
253-256c
215c
250c
205c
224-226c
251-253c
209-211c
222-226c
228-232c
183
C15H15N4O3Br‚2.0H2O
C21H20N4O3‚3.5H2O
43j
43k
43l
C21H19N4O3F‚3.0H2Oe
C21H19N4O3Cl
C21H19N4O3Cl
43m
43n
43o
44a
44b
44c
44d
44e
C
16H18N4O3‚1.9H2O‚0.5AcOH
223-225c
196-197
ndb
C15H15N4O3F‚2H2O‚0.1AcOH
C
15H15N4O3Cl‚2.5H2O
same as 44b
20a ; R, H, V, N, W, X, Y
same as 42p
same as 42q
commercially available
C13H14N4O3S‚1.3H2O
228-232c
210
C13H14N4O3S‚1.0H2O‚0.01AcOH
C
C
14H16N4O3S‚1.2H2O
14H16N4O4‚0.7H2O
190
240c
C12H12N4O4Na‚1.0H2O‚0.1AcOH
a
Analyses for C, H, N were within (0.4% of the theoretical values, unless otherwise stated. b Not determind, very deliquescent compound.
c Decomposed. Calcd: C, 54.16; H, 6.79; N, 14.86. Found: C, 53.91; H, 6.28; N, 14.57. e Calcd: C, 56.24; H, 5.62; N, 12.49. Found: C,
d
56.67; H, 5.20; N, 12.18.
Sch em e 7a
Sch em e 8a
9
Reagents: (a) Pd(PPh3)4, MeOH, CO, Et3N; (b) P+Ph3CH3Br-,
n-BuLi, THF; (c) n-BuLi, THF, ClCO2CH3; (d) vinyltributyltin,
Pd(PPh3)4, DMF; (e) 9-BBN, THF; 30% H2O2, 3 N NaOH; (f) CBr4,
PPh3, CH2Cl2.
a
a
Reagents: (a) i. allyl bromide, K2CO3, acetone, ii. BCl3, PhCl;
(b) i. O3, MeOH; NaBH4, ii. TBDMSCl, imidazole, DMF; (c) i. Tf2O,
Et3N, THF, ii. allyltributyltin or vinyltributyltin, Pd(PPh3)2Cl2,
PPh3, LiCl, DMF; (d) 10% Pd/C, H2, EtOAc; (e) CSA, MeOH,
CH2Cl2; (f) CBr4, PPh3, CH2Cl2.
a heteroaromatic ring such as furan or thiophene (e.g.
44b, AMPDA Ki ) 2.2 µM; Table 5) resulted in a
decrease in affinity as compared to the phenyl spacer
analogues with the same tether (e.g. 42s, AMPDA Ki )
0.5 µM). The carboxylic esters were also tested as
AMPDA inhibitors (Table 6). None of these esters (45a -
y) were as potent as their corresponding parent acids,
but in some cases they showed strong ADA binding
affinity, especially when there was a three-carbon tether
phenyl ring showed some decrease in potency as com-
pared to analogues with hydrophobic substituents.
Compounds with a halogen at the C4, 43n and 43o,
were more potent than the corresponding hydrogen or
the methyl analogues 42s and 43m , respectively (Table
4).
Replacement of the phenyl ring in the side chain with

1512 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8
Kasibhatla et al.
Ta ble 2. Physical Data and Methods of Preparation of AMPDA and ADA Inhibitors (Esters)
compd
mp (°C)
starting material; methods
formulaa
anal.
45a
45b
45c
45d
45e
45f
45g
45h
45i
185-186
170-171
119-120
188-189b
143-144
199-201
80-85
commercially available
commercially available
7; A, J , B, N, W, X
commercially available
24f; J , M, N, W, X
C
C
C
15H16N4O3‚0.25H2O
16H18N4O3‚0.25H2O
17H20N4O3‚0.5H2O
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C16H18N4O3
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
16H18N4O3‚0.25H2O
17H20N4O3
23H24N4O3
24a ; J , M, N, W, X
24a ; J , M, N, W, X
164-165
190-195
141-143
160-162
132-133
155-156
144-145
165-170
144-145
131-132
168-170
140-145
165-168
205-206
164-165
98-100
28; Q, M, R, S, L, T, N, W, X
24c; J , M, N, W, X
24e; J , K, J , L, N, W, X
24e; J , K, N, W, X, U
24e; J , K, N, W, X
19H24N4O3‚0.7H2O
17H20N4O4‚0.2H2O
19H24N4O3‚0.3H2O
23H24N4O3‚0.5H2O
17H19N4O3‚0.5H2O
18H22N4O3‚0.25H2O
17H20N4O3‚0.25H2O
18H22N4O3
18H22N4O3‚0.15H2O
17H19N4O3‚0.25H2O
20H26N4O3‚1.2H2O
17H20N4O3
18H22N4O3‚0.5H2O
18H23N5O2‚1.05H2O
18H22N4O4
21H22N4O3‚1.0H2O
16H18N4O4‚0.5H2O
16H18N4O3S
45j
45k
45l
45m
45n
45o
45p
45q
45r
45s
45t
45u
45v
45w
45x
45y
3b; O, H, P, N, W, X
14e; D, L, N, W, X
13a ; A, C, L, N, W, X
13b; A, C, L, N, W, X
14f; A, D, L, N, W, X
13c; A, C, L, N, W, X
14g; D, L, N, W, X
14h ; A, D, L, N, W, X
14h ; A, D, L, N, W, X (amide)
14i; D, L, N, W, X
13e; A, C, L, N, W, X
18a ; A, F, W, X
18c; A, F, W, X
180-181
179-180
a
b
Analyses for C, H, N were within (0.4% of the theoretical values, unless otherwise stated. Decomposed.
Sch em e 9a
acid on the phenyl ring. By stepwise variation of these
two parameters we identified 10-100-fold more potent
inhibitors. For example, compound 42s with a two-
carbon atom tether (X ) -(CH2)2-) and a m-carboxylic
acid on the phenyl ring was a 9-fold more potent
inhibitor of AMPDA than the lead inhibitor 2. In
contrast, compounds in which the carboxylic acid was
in the ortho and para positions (5-6 atoms from the
heterocycle to the carboxylic acid group, Table 3) showed
weak AMPDA affinity. Compound 42m showed that
replacement of the carboxylic acid group in 42s with
acetic acid resulted in a 20-fold decrease in potency.
Similarly, the m-carboxylic acid group with a three-
carbon atom tether (42o) showed decreased potency.
These results suggested that the relative position of the
carboxylic acid group was crucial to potency.10
a
Reagents: (a) R5B(OH)2, Pd(PPh3)4, Na2CO3, ethanol, diglyme
(40a ); (b) TBAF, THF (40b).
We next examined the effect of substitutions on the
phenyl ring in order to further improve the potency of
42s through optimization of hydrophobic and hydro-
philic interactions. Hydrophobic substituents at the C5
and C6 produced the most potent compounds. Small
hydrophobic substituents such as methyl or ethyl at the
C5 or C6 of the phenyl ring provided compounds 50-
100-fold more potent than compound 2 (e.g. 43a ,g). In
contrast, a methyl substituent at the C4, i.e. 43m , did
not have any effect on potency, suggesting that hydro-
phobic space is confined to the region near the C5 and
C6 of the phenyl ring in the active site. Analogues with
a bromine or phenyl substituent at the C5 were also
well-tolerated, indicating that the hydrophobic space in
this region is relatively large. The n-propyl substituent
at the C6 of the phenyl ring was also well-accepted.
Interestingly, halide substituents in the C4 (43n ,o)
provided a 2-3-fold improvement over the hydrogen
analogue (42s) or its methyl analogue (43m ). This might
suggest that these electron-withdrawing substituents
enhance potency by decreasing the pKa of the carboxylic
acid thus increasing the electrostatic interactions with
the phosphate binding site.
(e.g. 45o,t). Small substituents such as methyl on the
phenyl ring enhanced ADA affinity up to 4-fold (e.g. 45p ,
AMPDA Ki ) 1.6 µM and ADA Ki ) 0.04 µM). Similar
results were also observed with an amide 45u .9
Discu ssion
N3-Substituted coformycin aglycon analogues con-
taining a terminal carboxylic acid were previously
postulated to inhibit AMPDA through a combination of
transition-state binding interactions with the hetero-
cycle binding site and an electrostatic interaction be-
tween the carboxylic acid group and the phosphate
binding site.2 The preceding paper3 showed that ana-
logues with a five- or six-carbon spacer between N3 and
the carboxylate resulted in AMPDA inhibition with high
specificity. This work investigated the effect of introduc-
ing structural rigidity into the flexible side chain of the
lead compound 2, through the incorporation of a phenyl
ring between the N3 and the carboxylate.
Two variables required optimization, namely the
length of the alkyl tether between the diazepine base
and the phenyl ring and the position of the carboxylic

AMP Deaminase Inhibitors. 3
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8 1513
Ta ble 3. AMPDA and ADA Inhibition Constants
Ki (µM)
compd
X
R2
R3
R4
R5
R6
AMPDA
ADA
6.1
5.2
>7.5
>7.5
>7.5
1.8
42a
42b
42c
42d
42e
42f
42g
42h
42i
42j
42k
42l
42m
42n
42o
42p
42q
42r
42s
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)2-O-
-(CH2)2-S-
-(CH2)2-S-
-CH2-
CO2Na
CO2H
CO2H
CO2H
CO2H
CO2H
CO2Na
CO2Na
CO2H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
12.5
24
11.8
9
83.1
6.3
31.3
4.5
i-Pr
R5, R6 ) ring (Ph)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
270.3
>500
i-Pr
H
>125
>125
92.2
11.2
44.1
31.8
23.5
5.2
>7.5
>7.5
CO2Na
CH2CO2Na
-CH2-
-CH2-
H
H
H
H
H
H
H
H
H
H
H
H
>500
CH2CO2H
CH2CO2Na
CO2Na
CO2Na
CO2Na
CO2H
H
H
H
H
H
H
H
H
>7.5
-(CH2)2-
-(CH2)2-O-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-CH2-CC-
-(CH2)2-
>500
>7.5
2.4
H
Me
OMe
H
1.2
5.6
2.3
>7.5
4.2
CO2Na
CO2H
>125
H
H
0.51
Ta ble 4. m-Carboxyphenethyl SAR
Ta ble 5. Heteroaromatic Spacer SAR
Ki (µM)
Ki (µM)
AMPDA ADA
compd
R4
R5
R6
AMPDA
ADA
compd
Y
X
substn at carbon
42s
43a
43b
43c
43e
43f
43g
43h
43i
43j
43k
43l
43m
43n
43o
H
H
H
H
H
H
H
H
H
H
H
H
Me
F
H
H
H
H
H
H
H
Me
OMe
CH2OH
0.51
0.10
0.48
0.35
0.08
0.19
0.06
0.08
0.07
0.19
0.29
0.18
0.57
0.16
0.22
>7.5
>100
>7.5
>7.5
>7.5
>7.5
>7.5
>7.5
>7.5
>7.5
>7.5
>7.5
>7.5
>7.5
>7.5
44a
44b
44c
44d
44e
S
S
S
O
O
-(CH2)2-
-(CH2)2-
-(CH2)3-
-(CH2)3-
-CH2-
5
4
3
5
5
9.5
2.2
4.8
13.3
72.0
>7.5
>7.5
1.4
>7.5
>3.4
Et
Pr
H
H
H
H
H
H
H
H
H
Et
Br
Ph
p-FPh
p-ClPh
m-ClPh
H
favorable interactions between the π electron cloud of
the aromatic ring and the binding site.
Su m m a r y
H
H
The data presented here demonstrate that introduc-
tion of an appropriately positioned phenyl ring into the
side chain of compound 2 can significantly enhance
AMPDA inhibitory potency (42s). Inhibition was de-
pendent on the chain length of the linker tethering the
diazepine base to the phenyl ring as well as the relative
position of the carboxylic acid functionality on the
phenyl ring. Analogues with a two-carbon tether and a
carboxylic acid group at the meta position exhibited
inhibitory potencies ranging from 0.5-0.06 µM. Com-
pounds with small hydrophobic substituents at the C5
and C6 of the phenyl ring exhibited the highest potency,
suggesting the presence of a nearby hydrophobic pocket
in the active site.
Cl
Analogous to the earlier study,3 carboxylic esters are
much weaker inhibitors of AMPDA when compared to
their corresponding acids. Interestingly, o- and m-alkyl
esters, especially those with a three-carbon tether on
the phenyl ring, showed high ADA affinity.9
These results support the postulate that incorporation
of an aryl group between N3 and the carboxylate
provides additional inhibitory potency by restricting the
rotational freedom of the alkyl side chain of compound
2. Alternately, the enhanced affinity may result from

1514 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8
Ta ble 6. Carboxylate Ester SAR
Kasibhatla et al.
Ki (µM)
compd
X
R2
R3
R4
R5
R6
AMPDA
170
92.6
15.9
160
16
11
8.1
14
21
6.6
18
2.7
12
32.7
38
1.6
1.5
14
24.3
22
19.8
52.8
8.3
60.6
37.9
ADA
45a
45b
45c
45d
45e
45f
45g
45h
45i
-CH2-
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CO2Me
CH2CO2Me
H
H
H
H
H
H
H
H
H
H
H
H
H
8.7
6.7
5.6
-CH2-
-CH2-
CH2CO2Et
H
H
-(CH2)2-
-(CH2)2-
-(CH2)2-
-(CH2)2-
-(CH2)2-
-(CH2)2-
-(CH2)2-
-(CH2)2-
-(CH2)2-
-(CH2)2-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)2-O-
-(CH2)2-S-
CO2Me
H
81
CO2Me
CO2Et
CO2Bn
CO2Me
CO2Me
CO2Et
CO2Et
CO2Et
CO2Et
H
>7.5
>7.5
2.6
3.8
>7.5
8.9
>7.5
>7.5
>7.5
0.16
0.06
0.04
0.32
>7.5
0.16
0.08
0.05
0.13
0.18
2.3
H
H
H
H
H
H
H
Me
H
H
Me
H
H
H
H
H
H
H
Me
Me
Pr
OMe
H
H
45j
45k
45l
Et
Ph
Br
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
45m
45n
45o
45p
45q
45r
45s
45t
45u
45v
45w
45x
45y
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
H
H
H
F
H
i-Pr
H
Me
Me
OMe
CO2Me
CO2Me
CO2NHMe
CO2Me
H
H
H
H
H
H
CO2Me
CO2Me
CO2Me
R5, R6 ) ring (Ph)
H
H
H
H
H
H
H
H
11.9
N-methylmorpholine N-oxide (2.88 g, 24.6 mmol) followed by
OsO4 (12.5 mL, 1.0 mmol; 2.5 wt % in t-BuOH). After stirring
at room temperature for 7 h, NaHCO3 (20.6 g, 246 mmol),
NaIO4 (13.9 g, 65.1 mmol) and 280 mL of H2O were added.
The heterogeneous mixture was stirred for 45 min before it
was poured onto a saturated solution of Na2SO3. The mixture
was extracted with ether and dried (MgSO4). Evaporation of
the solvent provided 4.16 g (104%, slightly impure) of ethyl
(3-formylphenyl)acetate as an amber-colored oil: 1H NMR
(CDCl3) δ 1.26 (t, 3H, J ) 7.0 Hz), 3.7 (s, 2H), 4.19 (q, 2H, J
) 7.12 Hz), 7.4-7.6 (m, 2H), 7.7-7.9 (m, 2H), 10.0 (s, 1H).
The residue was used as is for the next step.
Exp er im en ta l Section
Gen er a l Meth od s. Glassware for moisture-sensitive reac-
tions was flame-dried and cooled to room temperature in a
desiccator and all reactions were carried out under an atmo-
sphere of nitrogen. Anhydrous solvents were purchased from
Aldrich and stored over 4 Å molecular sieves. THF was freshly
distilled from Na/benzophenone ketyl under nitrogen. Flash
chromatography was performed on 230-400 mesh EM Science
silica gel 60. Melting points were recorded on a Thomas-Hoover
capillary melting point apparatus and are uncorrected. 1H
NMR spectra were obtained on a Varian Gemini-200 operating
at 200 MHz and recorded in units δ with tetramethylsilane (δ
0.00) as a reference line internal standard. C, H, N micro-
analyses were performed by Robertson Microlit Laboratories,
Inc., Madison, NJ .
To the ethyl (3-formylphenyl)acetate (3.92 g, 20.4 mmol) in
40 mL of MeOH was added NaBH4 (0.76 g, 20.1 mmol) at 0
°C and the resulting solution was stirred at room temperature
for 1 h. The reaction mixture was quenched with acetone (0.5
mL) and the solvent was removed under reduced pressure. The
residue was diluted with water (25 mL) and extracted with
CH2Cl2 (350 mL). The combined organic layers were washed
with water and brine and dried (MgSO4). The solvent was
removed and the residue was purified by chromatography (40%
EtOAc in hexane) to yield 3.49 g (88%) of ethyl (3-hydroxy-
methylphenyl)acetate (10) as a clear oil: 1H NMR (CDCl3) δ
1.25 (t, 3H, J ) 7.0 Hz), 3.62 (s, 2H), 4.17 (q, 2H, J ) 7.12
Hz), 4.68 (d, 2H, J ) 5.9 Hz), 7.2-7.4 (m, 4H).
Gen er a l P r oced u r e C. P r op a r gyla tion of P h en ols:
Meth yl 2-(3-Hydr oxypr op-1-yn yl)-4-m eth ylben zoate (15a).
To a solution of methyl 2-hydroxy-4-methylbenzoate (13a ) (3.2
g, 19.1 mmol) and TEA (10.0 mL, 71.7 mmol) in 20 mL of THF
cooled to -78 °C was added slowly trifluoromethanesulfonic
anhydride (4 mL, 23.8 mmol) and the mixture was allowed to
come to room temperature. Upon completion of the reaction
by TLC, solvent was evaporated under reduced pressure and
the crude residue was used as is for the next step.
En zym e Assa ys. The AMPDA and ADA Ki determinations
were performed as previously described.2
The following general procedures are illustrative.
Gen er a l P r oced u r e A. Ester ifica tion of Ar om a tic a n d
Alip h a tic Acid s: Eth yl (3-Br om op h en yl)a ceta te (8). To
a solution of 3-bromophenylacetic acid (7) (10.17 g, 47.3 mmol)
in 150 mL of EtOH was added concentrated H2SO4 (5.3 mL,
95.4 mmol). The reaction mixture was refluxed for 96 h.
Solvent was removed by distillation and the residue was
diluted with 200 mL of water and extracted with ether (2 ×
200 mL). The combined organic layers were washed with
water, saturated NaHCO3 (3 × 100 mL) and dried (MgSO4).
Removal of solvent provided 11.3 g (98%) of ethyl (3-bro-
mophenyl)acetate (6) as a light yellow liquid: 1H NMR (CDCl3)
δ 1.26 (t, 3H, J ) 7.1 Hz), 3.57 (s, 2H), 4.16 (q, 2H, J ) 7.1
Hz), 7.2 (m, 2H, J ) 1.8 Hz), 7.4 (m, 2H).
Gen er a l P r oced u r e B. OsO4 Oxid a tion of Olefin : Eth yl
(3-Hyd r oxym eth ylp h en yl)a ceta te (10). To a solution of
ethyl (3-vinylphenyl)acetate (9) (3.9 g, 20.5 mmol) in 120 mL
of t-BuOH, 40 mL of THF and 12 mL of H2O was added
The crude triflate was dissolved in 50 mL of DMF and

AMP Deaminase Inhibitors. 3
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8 1515
(PPh3)2Pd(Cl)2 (1.3 g, 1.9 mmol), propargyl alcohol (2.3 mL,
40.0 mmol) and Et3N (5.6 mL, 40.0 mmol) were added. The
resultant mixture was heated at 60 °C. Upon completion of
the reaction by TLC, the solvent was evaporated under reduced
pressure. The residue was diluted with ether (80 mL), washed
with 0.1 N HCl (2 × 10 mL) and water (2 × 15 mL), and dried
(MgSO4). The solvent was removed and the residue was
purified by chromatography (25% EtOAc in hexane) to give
2.2 g (56%) of methyl 2-(3-hydroxyprop-1-ynyl)-4-methylben-
zoate (15a ): 1H NMR (CDCl3) δ 2.1 (t, 3H, J ) 5.1 Hz,
exchangeable with D2O), 2.36 (s, 3H), 3.9 (s, 3H), 4.56 (d, 2H,
J ) 6.1 Hz), 7.17 (br d, 1H, J ) 8.1 Hz), 7.37 (br s, 1H), 7.85
(br d, 1H, J ) 8.1 Hz).
Gen er a l P r oced u r e D. P r op a r gyla tion of Ar om a tic
Ha lid es: Meth yl 2-F lu or o-6-(3-h yd r oxyp r op -1-yn yl)ben -
zoa te (15f). To a solution of methyl 6-fluoro-2-iodobenzoate
(14f) (8.8 g, 31.4 mmol) in 125 mL of Et2NH under N2 were
added Pd(PPh3)2Cl2 (1.1 g, 1.6 mmol), CuI (0.2 g, 1.1 mmol)
and propargylic alcohol (3.5 mL, 60.1 mmol). The resulting
mixture was stirred for 6 h at which time the reaction was
complete by TLC. Solvent was removed under reduced pres-
sure and the residue diluted with ether (200 mL). The ethereal
solution was washed with water (2 × 30 mL) and 0.1 N HCl
(2 × 20 mL) and dried (MgSO4). The solvent was evaporated
and the residue purified by chromatography (50% EtOAc in
hexane) to give 5.8 g (91%) of methyl 2-fluoro-6-(3-hydrox-
yprop-1-ynyl)benzoate (15f) as a brown oil: 1H NMR (CDCl3)
δ 3.96 (s, 3H), 4.5 (s, 2H), 7.1 (m, 1H), 7.3 (m, 2H).
Gen er a l P r oced u r e E. Ca r boxyla tion of Th iop h en ols:
3-Isop r op ylth iosa licylic Acid (18e). To a solution of n-BuLi
(43 mL, 68.8 mmol) and TMEDA (10 mL, 66.3 mmol) in 70
mL of cyclohexane was added 2-isopropylthiophenol (18d ) (4.6
mL, 30.4 mmol) at 0 °C. The mixture was warmed to room
temperature and stirred for 24 h. The orange solution was
added via cannula to a large excess of powdered dry ice and
the resultant red solution was stirred at room temperature
for 16 h. The reaction mixture was diluted with 1 N HCl until
the aqueous layer was acidic and extracted with ether (3 × 50
mL). The combined organic layers were washed with water
and dried (MgSO4). The solvent was removed and the residue
was purified by chromatography (15% MeOH in CH2Cl2) to
give 4.0 g (68%) of 3-isopropylthiosalicylic acid (18e) as a green
solid: mp 75 °C; 1H NMR (CD3OD) δ 1.23 (d, 6H, J ) 6.8 Hz),
3.38 (m, 1H), 7.1 (t, 1H, J ) 7.8 Hz), 7.35 (d, 1H, J ) 6.4 Hz),
7.88 (d, 1H, J ) 9.2 Hz).
Gen er a l P r oced u r e F . O- or S-Alk yla tion of P h en ols
or Th iop h en ols Usin g K2CO3: Meth yl 2-(2-Br om oeth oxy)-
ben zoa te (19a ). To a solution of methyl salicylate (18a ) (3.9
mL, 30.1 mmol) in 30 mL of DMSO was added K2CO3 (8.8 g,
63.7 mmol) followed by 1,2-dibromoethane (5.2 mL, 60.3
mmol). After 3.5 h at room temperature the mixture was
diluted with water (100 mL) and extracted with ether (240
mL). The combined organic layers were washed with water
and dried (MgSO4). The solvent was removed and the residue
was purified by chromatography (25% EtOAc in hexane) to
t h iop h en eca r b oxyla t e (21a ). To a solution of 3-(tert-but-
yldimethylsilyloxyethyl)thiophene (20b) (6.8 g, 28.0 mmol) in
50 mL of dry THF was added n-BuLi (3.4 mL, 34.0 mmol)
slowly at -78 °C under N2 and the mixture was stirred for 5
h at which time the reaction had reached ambient tempera-
ture. The resulting enolate solution was again cooled to -78
°C, methyl chloroformate (2.6 mL, 33.6 mmol) was added, and
the mixture was allowed to stir at room temperature for 16 h.
The reaction mixture was slowly quenched with water and
diluted with 200 mL of ether. The ether layer was washed with
water and brine and dried (MgSO4). The solvent was removed
and the residue was purified by chromatography (5% EtOAc
in hexane) to give 5.3 g (63%) of the product mixture methyl
4-(tert-butyldimethylsilyloxyethyl)-2-thiophenecarboxylate and
methyl 3-(tert-butyldimethylsilyloxyethyl)-2-thiophenecarboxy-
late. Although a small Rf difference by TLC was evident, they
could not be separated by chromatography. However, from one
of the column fractions a small amount of the pure required
regioisomer, methyl 4-(tert-butyldimethylsilyloxyethyl)-2-
thiophenecarboxylate (21a ) was isolated for the NMR identi-
fication: 1H NMR (CDCl3) δ 0.0 (s, 6H), 0.87 (s, 9H), 2.8 (t,
2H, J ) 6.58 Hz), 3.8 (t, 2H, J ) 6.54 Hz), 3.87 (s, 3H), 7.24
(d, 1H,J ) 1.4 Hz), 7.67 (d, 1H, J ) 1.5 Hz).
P r oced u r e I. Eth yl 3-Br om o-4-(ter t-bu tyld im eth ylsil-
yloxym eth yl)ben zoa te (24b). A mixture of ethyl 3-bromo-
4-methylbenzoate (24a ) (12.0 g, 49.37 mmol), N-bromosuccin-
amide (8.2 g, 46.0 mmol) and a catalytic amount of benzoyl
peroxide (100 mg) in 150 mL of CCl4 was refluxed for 8 h. The
resulting suspension was filtered to remove the byproducts.
The filtrate was diluted with CH2Cl2 (600 mL), washed with
water, NaHCO3, dried (MgSO4) and evaporated to give 8.2 g
of crude product. This crude mixture, of which the major
component was the required ethyl 3-bromo-4-bromomethyl-
benzoate, was used directly in the next reaction without
further purification.
To a solution of ethyl 3-bromo-4-(bromomethyl)benzoate in
(7.25 g, 22.5 mmol, crude from step 1) in 100 mL of dioxane
was added a solution of CaCO3 (10 g, 100 mmol) in 100 mL of
H2O. The resultant milky white suspension was heated at 100
°C for 12 h, and the solvent was removed under vacuum. The
residue was diluted with EtOAc (300 mL), washed with water
and brine, dried (MgSO4) and concentrated. The crude product
was purified by column chromatography (10% followed by 40%
EtOAc in hexane) to give 4.3 g of ethyl 3-bromo-4-(hydroxy-
methyl)benzoate as an oil: 1H NMR (CDCl3) δ 1.39 (t, 3H, J
) 7.1 Hz), 2.2 (t, 1H, J ) 5.8 Hz, exchangeable with D2O),
4.37 (q, 2H, J ) 7.1 Hz), 4.8 (d, 2H, J ) 5.8 Hz), 7.59 (d, 1H,
J ) 8.0 Hz), 7.95 (dd, 1H, J 1 ) 8.0 Hz, J 2 ) 1.7 Hz), 8.2 (d,
1H, J ) 1.7 Hz).
A mixture of ethyl 3-bromo-4-(hydroxymethyl)benzoate (8.6
g, 33.2 mmol), tert-butyldimethylsilyl chloride (5.0 g, 33.2
mmol), and imidazole (4.5 g, 66.4 mmol) in 200 mL of DMF
was stirred at room temperature for 45 min. The reaction
mixture was diluted with ether (400 mL), washed with water
(3 × 60 mL) and brine and dried (MgSO4). The solvent was
evaporated to give 12.0 g (98%) of ethyl 3-bromo-4-(tert-
butyldimethylsilyloxymethyl)benzoate (24b) that was used
directly in the next reaction without further purification: 1H
NMR (CDCl3) δ 0.1 (s, 6H), 0.93 (s, 9H), 1.32 (t, 3H, J ) 7.0
Hz), 3.4 (d, 2H, J ) 6.2 Hz), 4.31 (q, 2H, J ) 7.0 Hz), 7.61 (d,
1H, J ) 7.9 Hz), 7.87 (d, 1H, J ) 7.9 Hz), 8.22 (br s, 1H).
give 2.0
g (26.5%) of methyl 2-(2-bromoethoxy)benzoate
(19a ): 1H NMR (DMSO-d6) δ 3.78 (t, 2H, J ) 5.2 Hz), 3.80 (s,
3H), 4.4 (t, 2H, J ) 5.3 Hz), 7.0-7.2 (m, 2H), 7.4-7.7 (m, 2H).
Gen er a l P r oced u r e G. O- or S-Alk yla tion Usin g Mit-
su n ob u Met h od : Met h yl 3-(2-Br om oet h oxy)b en zoa t e
(19b). To a mixture of methyl 3-hydroxybenzoate (18b) (1.8
g, 11.7 mmol), PPh3 (6.6 g, 26.1 mmol) and 2-bromoethanol
(1.8 mL, 25.9 mmol) in 40 mL of THF was added DEAD (4.0
mL, 26.1 mmol) slowly dropwise at 0 °C. The resultant mixture
was stirred at room temperature for 16 h and the solvent was
evaporated. The residue was diluted with ether (80 mL),
washed with water (2 × 20 mL) and dried (MgSO4). The
solvent was removed and the residue was purified by chro-
matography (CH2Cl2) to give 1.6 g (53%) of methyl 3-(2-
bromoethoxy)benzoate (19b) as a yellow oil: 1H NMR (DMSO-
d6) δ 3.83 (t, 2H, J ) 5.2 Hz), 3.86 (s, 3H), 4.4 (t, 2H, J ) 5.2
Hz), 7.2-7.7 (m, 4H).
Gen er a l P r oced u r e J . Allyla tion or Vin yla tion of th e
Ar om a tic Ha lid es: Meth yl 3-P r op en ylben zoa te (24f). To
a solution of methyl 3-bromobenzoate (14.95 g, 69.5 mmol) in
200 mL of dry DMF under nitrogen were added Pd(PPh3)4 (4.15
g, 3.6 mmol) and allyltributyltin (26 mL, 84.0 mmol). The
mixture was degassed with N2 for 5 min and heated at 80 °C
for 36 h. NMR analysis indicated complete reaction. After
cooling, it was partitioned between ether and brine. The
organic phase was stirred over 10% aqueous NaF solution for
4 h. The ether layer was separated, washed with water and
brine and dried (MgSO4). The solvent was removed and the
residue was purified by chromatography (5% EtOAc in hexane)
to give 10.3 g (85%) of methyl 3-propenylbenzoate (25f) as an
Gen er a l P r oced u r e H. Ca r boxyla tion of th e Ar om a tic
R in gs: Met h yl 4-(ter t-Bu t yld im et h ylsilyloxyet h yl)-2-

1516 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8
Kasibhatla et al.
oil: 1H NMR (CDCl3) δ 3.43 (d, 2H, J ) 6.8 Hz), 3.91 (s, 3H),
was heated at 90 °C at 40 psi CO pressure in bomb for 16 h.
After cooling, it was partitioned between ether and brine. The
ether layer was separated, washed with water and brine and
dried (MgSO4). The solvent was removed and the residue
purified by chromatography (10% EtOAc in hexane) to give
4.0 g of starting material and 4.0 g (50%) of methyl 2-fluoro-
5-formylbenzoate as an oil: 1H NMR (CDCl3) δ 3.97 (s, 3H),
7.3 (dd, 1H, J 1 ) 10.6 Hz, J 2 ) 8.6 Hz), 8.1 (m, 1H), 8.47 (dd,
1H, J 1 ) 7.1 Hz, J 2 ) 2.1 Hz), 10.0 (s, 1H).
To a suspension of methyltriphenylphosphonium bromide
(5.88 g, 16.46 mmol) in 50 mL of THF under N2 was added
n-BuLi (8.2 mL, 13.12 mmol, 1.6 mmol in hexane) slowly at 0
°C. After stirring for 1.5 h at 0 °C, a solution of methyl 2-fluoro-
5-formylbenzoate (2.0 g, 10.98 mmol) in 10 mL of THF was
added to the yellow syrup. The resultant light yellow mixture
was stirred for additional 3 h at room temperature and was
diluted with ether (200 mL). The ether layer was washed with
water and brine and dried (MgSO4). The solvent was removed
and the residue purified by chromatography (10% EtOAc in
hexane) to give 0.8 g (40%) of methyl 2-fluoro-5-vinylbenzoate
(37a ) (16 h) as an oil: 1H NMR (CDCl3) δ 3.94 (s, 3H), 5.3 (d,
1H, J ) 10.7 Hz), 5.74 (d, 1H, J ) 17.58 Hz), 6.7 (dd, 1H, J 1
) 10.9 Hz, J 2 ) 17.6 Hz), 7.1 (dd, 1H, J 1 ) 10.8 Hz, J 2 ) 8.5
Hz), 7.55 (m, 1H), 7.96 (dd, 1H, J 1 ) 6.9 Hz, J 2 ) 2.0 Hz).
Gen er a l P r oced u r e P . 9-BBN Oxid a tion of th e Vin yl-
ar yls: Meth yl 2-Flu or o-5-(2-h ydr oxyeth yl)ben zoate (38a).
To a solution of 9-BBN dimer (1.62 g, 6.66 mmol) in 10 mL of
THF was added a solution of methyl 2-fluoro-5-vinylbenzoate
(37a ) (0.8 g, 4.44 mmol) in 20 mL of THF and the resulting
solution was stirred for 16 h. The solution was cooled to -30
°C and slowly treated with 30% H2O2 (1.5 mL, 13.5 mmol),
followed by 3 N NaOH (2.3 mL, 7.0 mmol). The reaction was
allowed to warm to 0-10 °C and stirred for 1 h at which time
the heterogeneous solution was diluted with water (50 mL)
and extracted with ether (3 × 50 mL). The combined ether
layers were washed with water and brine and dried (MgSO4).
The solvent was removed and the residue was purified by
chromatography (30% EtOAc in hexane) to give 0.44 g (50%)
of methyl 2-fluoro-5-(2-hydroxyethyl)benzoate (38a ) as an
oil: 1H NMR (CDCl3) δ 1.44 (t, 1H, J ) 5.8 Hz, exchangeable
with D2O), 2.87 (t, 2H, J ) 6.3 Hz), 3.9 (s, 3H), 3.85 (q, 2H, J
) 5.86 Hz), 7.1 (dd, 1H, J 1 ) 10.5 Hz, J 2 ) 8.5 Hz), 7.4 (m,
1H), 7.8 (dd, 1H, J 1 ) 6.9 Hz, J 2 ) 2.2 Hz).
P r oced u r e Q. Meth yl 3-(2-P r op en yl)-4-h yd r oxyben -
zoa te (29). To a solution of methyl 4-hydroxybenzoate (28)
(15.23 g, 0.10 mol) in 200 mL of acetone under N2 was added
allyl bromide (17.3 mL, 0.20 mol) followed by K2CO3 (69.71 g,
0.50 mol) slowly at 0 °C. The resulting suspension was stirred
for 16 h, and the solvent removed under vacuum. The residue
was diluted with ether (500 mL), washed with water and brine,
dried (MgSO4) and concentrated under reduced pressure to
give 21.96 g of methyl 4-(3-propenyloxy)benzoate as an oil. The
crude mixture was used directly in the next reaction without
further purification: 1H NMR (CDCl3) δ 3.8 (s, 3H), 4.58 (dd,
2H, J 1 ) 5.3 Hz, J 2 ) 1.5 Hz), 5.3(m, 2H), 6.0 (m, 1H), 6.9 (d,
2H, J ) 8.9 Hz), 7.9 (d, 2H, J ) 8.9 Hz).
5.1 (m, 2H), 5.9 (m, 1H), 7.37 (m, 2H), 7.87 (m, 2H).
Gen er a l P r oced u r e K. Na IO4 Oxid a tion of th e Ar yl-
p r op en yls: Eth yl 3-Br om o-5-(2-h yd r oxyeth yl)ben zoa te
(26e). To a solution of ethyl 3-bromo-5-(1-propenyl)benzoate
(25e) (1.0 g, 3.88 mmol) in a mixture of solvents CCl4 (4 mL),
CH3CN (4 mL), and H2O (6.0 mL) were added NaIO4 (2.0 g,
9.55 mmol) and RuO2 (56.2 mg, 0.42 mmol) and the resulting
dark mixture was stirred for 15 min. The reaction mixture was
diluted with water (15 mL) and extracted with CH2Cl2 (4 ×
30 mL). The combined organic layers were washed with water,
brine and dried (MgSO4). The solvent was removed and the
residue was used as is for the next step.
The crude aldehyde was taken into 5 mL of MeOH, NaBH4
(0.15 g, 4.16 mmol) was added at 0 °C, and the resulting
solution was stirred at room temperature for 1 h. The reaction
mixture was quenched with acetone (0.5 mL) and the solvent
was removed under reduced pressure. The residue was diluted
with water (15 mL) and extracted with CH2Cl2 (3 × 30 mL).
The combined organic layers were washed with water and
brine and dried (MgSO4). The solvent was removed and the
residue was purified by chromatography (40% EtOAc in
hexane) to give 0.33 g of ethyl 3-bromo-5-allylbenzoate and
0.25 g of ethyl 3-bromo-5-(2-hydroxyethyl)benzoate (26e) (36%,
based on the recovered starting material) as oils: 1H NMR
(CDCl3) δ 1.39 (t, 3H, J ) 7.6 Hz), 1.48 (t, 1H, J ) 6.2 Hz,
exchangeable with D2O), 2.89 (t, 2H, J ) 6.6 Hz), 3.9 (q, 2H,
J ) 6.2 Hz, collapsed to t with D2O), 4.37 (q, 2H, J ) 7.0 Hz),
7.58 (br s, 1H), 7.8 (br s, 1H), 8.0 (br s, 1H).
Gen er a l P r oced u r e L. Hyd r ogen a tion of Vin yl or Allyl:
Eth yl 3-Eth yl-5-(2-h yd r oxyeth yl)ben zoa te (26g). To a
solution of ethyl 3-vinyl-5-(2-hydroxyethyl)benzoate (0.36 g,
1.62 mmol) in 30 mL of EtOAc was added 10% Pd/C (0.1 g).
The mixture was hydrogenated at 30 psi H2 pressure for 1 h,
at which time NMR analysis indicated completion of the
reaction. The catalyst was filtered through Celite, and the
filtrate was evaporated to give 0.35 g (100%) of ethyl 3-ethyl-
5-(2-hydroxyethyl)benzoate (26g) as an oil: 1H NMR (CDCl3)
δ 1.26 (t, 3H, J ) 7.7 Hz), 1.4 (t, 3H, J ) 7.1 Hz), 2.68 (q, 2H,
J ) 7.5 Hz), 2.9 (t, 2H, J ) 6.4 Hz), 3.9 (m, 2H), 4.37 (q, 2H,
J ) 7.1 Hz), 7.26 (br s, 1H), 7.73 (br s, 1H), 7.76 (br s, 1H).
Gen er a l P r oced u r e M. Ozon olysis of th e Ar ylp r op en -
yls: Meth yl 3-(2-Hyd r oxyeth yl)ben zoa te (26f). A solution
of methyl 3-(2-propenyl)benzoate (25f) (10.0 g, 56.7 mmol) in
150 mL of MeOH was cooled to -78 °C. Ozone was bubbled
through the solution until a blue color developed. After 5 min,
the excess ozone was removed with a nitrogen purge, and
NaBH4 (32.3 g, 85.5 mmol) was added slowly at -78 °C. The
solution was allowed to warm to 20 °C and stirred for 14 h.
The solvent was removed under vacuum, and the residue
partitioned between ether and brine. The organic phase was
washed with water, dried and concentrated. The crude product
was purified by column chromatography (40% EtOAc in
hexane) to give 6.87 g of methyl 3-(2-hydroxyethyl)benzoate
(26f) (67%): 1H NMR (CDCl3) δ 1.51 (t, 1H, exchangeable with
D2O), 2.92 (t, 2H, J ) 6.5 Hz), 3.91 (s, 3H), 3.88 (q, 2H, J )
6.3 Hz, collapsed to t with D2O), 7.42 (m, 2H), 7.91 (m, 2H).
To a solution of methyl 4-(3-propenyloxy)benzoate (19.53 g,
0.10 mol) in 200 mL of chlorobenzene under N2 was added BCl3
(102 mL, 0.1 mol). After 8 h at room temperature the mixture
was poured on to ice (200 g) and extracted with ether (3150
mL). The combined ether layers were washed with water, dried
(MgSO4) and concentrated under reduced pressure to give a
brown residue of methyl 3-(2-propenyl)-4-hydroxybenzoate
(29). The crude mixture was used directly in the next reaction
without further purification: 1H NMR (CDCl3) δ 3.9 (s, 3H),
3.45 (d, 2H, J ) 7.1 Hz), 5.15 (m, 2H), 6.0 (m, 1H), 6.85 (d,
1H, J ) 8.9 Hz), 7.95 (m, 2H).
Gen er a l P r oced u r e R. TBDMS P r otection of th e Al-
coh ols: Met h yl 3-(2-ter t-Bu t yld im et h ylsilyloxy)-4-h y-
d r oxyben zoa te (30). A mixture of methyl 3-(2-hydroxyethyl)-
4-hydroxybenzoate (2.4 g, 12.2 mmol), tert-butyldimethylsilyl
chloride (2.03 g, 13.5 mmol), DMAP (0.15 g, 1.2 mmol) and
imidazole (1.01 g, 14.8 mmol) in 25 mL of DMF was stirred at
room temperature for 14 h then diluted with ether (60 mL)
Gen er al P r ocedu r e N. Halogen ation of Alcoh ols: Meth -
yl 3-(2-Br om oeth yl)ben zoa te (27f). To a solution of methyl
3-(2-hydroxyethyl)benzoate (26f) (6.2 g, 34.4 mmol) in 70 mL
of dry CH2Cl2 under N2 was added triphenylphosphine (11.0
g, 41.9 mmol) followed by carbon tetrabromide (13.69 g, 41.3
mmol) slowly at 0 °C. The resulting mixture was stirred for
30 min at which time TLC analysis indicated complete
reaction. The solvent was removed and the residue was
purified by chromatography (5% EtOAc in hexane) to give 8.0
g (96%) of methyl 3-(2-bromoethyl)benzoate (27f) as an oil: 1H
NMR (CDCl3) δ 3.22 (t, 2H, J ) 7.3 Hz), 3.59 (t, 2H, J ) 7.1
Hz), 3.92(s, 1H), 7.41 (m, 2H), 7.92 (m, 2H).
P r oced u r e O: Meth yl 2-F lu or o-5-vin ylben zoa te (37a ).
To a solution of 3-bromo-4-fluorobenzaldehyde (35a ) (14h, 9.0
g, 44.3 mmol) in 20 mL of dry DMF were added triethylamine
(10.0 mL, 71.7 mmol), MeOH (15 mL), and tetrakis(triph-
enylphosphine)palladium (2.5 g, 2.16 mmol), and the mixture

AMP Deaminase Inhibitors. 3
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8 1517
and washed with water. The aqueous layer was separated and
extracted with ether (3 × 30 mL). The combined ether layers
were washed with water and brine and dried (MgSO4). The
solvent was removed and the residue was purified by chro-
matography (5% EtOAc in hexane) to give 2.71 g (71%) of
methyl 3-(2-tert-butyldimethylsilyloxy)-4-hydroxybenzoate (30)
as an oil: 1H NMR (CDCl3) δ 0.1 (s, 6H), 0.9 (s, 9H), 2.92 (t,
2H, J ) 5.1 Hz), 3.9 (t, 2H, J ) 4.9 Hz), 3.87 (s, 3H), 6.92 (d,
1H,J ) 8.4 Hz), 7.75 (d, 1H, J ) 2.1 Hz), 7.1 (dd, 1H, J 1 ) 2.0
Hz, J 2 ) 8.4 Hz), 8.95(s, 1H).
Gen er a l P r oced u r e S. Allyla tion or Vin yla tion of th e
P h en ols: Meth yl 3-(2-ter t-Bu tyld im eth ylsilyloxyeth yl)-
4-vin ylb en zoa t e (31a ). A solution of methyl 3-(2-tert-but-
yldimethylsilyloxyethyl)-4-hydroxybenzoate (30) (1.26 g, 4.0
mmol) and triethylamine (3.3 mL, 23.7 mmol) in 15 mL of THF
was cooled to -78 °C and trifluoromethanesulfonic anhydride
(0.74 mL, 4.4 mmol) was added slowly and allowed to come to
room temperature. Upon completion of the reaction by TLC,
the solvent was evaporated under reduced pressure and the
residue was used as is for the next step.
fluoride (0.75 mL, 0.75 mmol; 1.0 M solution in THF) at 0 °C
and was stirred for 3 h. SiO2 (2.0 g) was added to the reaction
mixture and the solvent was removed. The powder was applied
to the top of a column and eluted with 12% methanol in CH2-
Cl2 to give 0.14 g (73%) of 3-(2-hydroxymethyl-5-carbethoxy-
phenethyl)coformycin aglycon (41e): 1H NMR (DMSO-d6) δ 1.3
(t, 3H, J ) 7.1 Hz), 2.9-3.2 (m, 4H), 3.9-4.2 (m, 2H), 4.29 (q,
2H, J ) 7.1 Hz), 4.7-5.0 (m, 2H), 7.0-7.9 (series m, 6H).
Gen er a l P r oced u r e W. Alk yla tion of th e Aglycon : 3-[2-
(3-Car beth oxy-6-m eth ylph en yl)eth yl]-6,7-dih ydr oim idazo-
[4,5-d ][1,3]d ia zep in -8(3H)-on e: According to the procedure
previously described3 ketone 3 (2.0 g, 13.4 mmol) was alkylated
with 27a (3.97 g, 14.63). Chromatography on SiO2 with a CH2-
Cl2/MeOH gradient of 20:1, 18:1 and 15:1 provided 1.77 g (39%)
of 3-[2-(3-carboxyethoxy-6-methylphenyl)ethyl]-6,7-dihydroimi-
dazo[4,5-d][1,3]diazepin-8(3H)-one as a light yellow solid: 1H
NMR (DMSO-d6) δ 1.3 (t, 3H, J ) 7.1 Hz), 2.3 (s, 3H), 3.1 (t,
2H, J ) 7.2 Hz), 3.74 (d, 2H, J ) 4.2 Hz), 4.2 (t, 2H, J ) 7.2
Hz), 4.3 (q, 2H, J ) 7.0 Hz), 7.3 (m, 1H), 7.46 (d, 1H, J ) 4.7
Hz), 7.5 (br s, 1H), 7.7 (m, 2H), 8.4 (m, 1H).
The crude triflate was dissolved in 10 mL of DMF and
(PPh3)2Pd(Cl)2 (0.4 g, 0.62 mmol), PPh3 (0.43 g, 1.6 mmol) and
LiCl (1.4 g, 32.9 mmol) were added followed by vinyltributyl
tin (2.5 mL, 8.06 mmol). The resultant mixture was heated at
90 °C for 14 h. The solvent was evaporated and the residue
was diluted with ether (60 mL), washed with water (210 mL)
and saturated NaF (2 × 10 mL) and dried (MgSO4). The
solvent was removed and the residue was purified by chro-
matography (5% EtOAc in hexane) to give 0.95 g (70%) of
methyl 3-(2-tert-butyldimethylsilyloxyethyl)-4-vinylbenzoate
(31a ): 1H NMR (CDCl3) δ -0.05 (s, 6H), 0.8 (s, 9H), 2.9 (t,
2H, J ) 6.9 Hz), 3.8 (t, 2H, J ) 6.9 Hz), 3.9 (s, 3H), 5.4 (d, 1H,
J ) 11 Hz), 5.7 (d, 1H, J ) 17.4 Hz), 7.1 (dd, 1H, J 1 ) 11 Hz,
J 2 ) 17.4 Hz), 7.53 (d, 1H, J ) 8.7 Hz), 7.8-7.9 (m, 2H).
Gen er a l P r oced u r e X. Red u ction : 3-[2-(3-Ca r beth oxy-
6-m eth ylp h en yl)eth yl]cofor m ycin Aglycon (45f). Accord-
ing to the procedure previously described3 3-[2-(3-carboxyethoxy-
6-methylphenyl)ethyl]-6,7-dihydroimidazo[4,5-d][1,3]diazepin-
8(3H)-one (1.77 g, 5.2 mmol) was reduced with NaBH4 (255
mg, 6.8 mmol). Chromatography on SiO2 with a CH2Cl2/MeOH
gradient of 20:1, 15:1 and 10:1 provided 1.3 g (73%) of 3-[2-
(3-carbethoxy-6-methylphenyl)ethyl]coformycin aglycon (45f)
as a light green solid: mp 148-150 °C; 1H NMR (DMSO-d6) δ
1.33 (t, 3H, J ) 7.0 Hz), 2.3 (s, 3H), 3.0 (t, 2H, J ) 7.1 Hz), 3.2
(m, 2H), 4.1 (m, 2H), 4.3 (q, 2H, J ) 7.0 Hz), 4.8 (m, 1H), 4.9
(d, 1H, J ) 5.3 Hz), 7.0 (d, 1H, J ) 4.4 Hz), 7.2 (s, 1H), 7.3 (d,
1H, J ) 8.4 Hz), 7.5 (m, 1H), 7.7 (m, 2H). Anal. (C18H22N4O3)
C, H, N.
Gen er a l P r oced u r e T. TBDMS Dep r otection Usin g
Ca m p h or su lfon ic Acid : Meth yl 3-(2-Hyd r oxyeth yl)-4-
p r op ylb en zoa t e (33b ). A mixture of methyl 3-(2-tert-but-
yldimethylsilyloxyethyl)-4-propylbenzoate (31b) (0.85 g, 2.54
mmol), camphorsulfonic acid (56.7 mg, 0.24 mmol), MeOH (3
mL), and CH2Cl2 (3 mL) was stirred at room temperature for
2 h at which time additional camphorsulfonic acid (54.3 mg,
0.23 mmol) was added in an attempt to make the reaction go
to completion. After 14 h at room temperature solvent was
removed and the residue was diluted with ether (60 mL),
washed with water (2 × 10 mL) and dried (MgSO4). The
solvent was removed and the residue was purified by chro-
matography (30% EtOAc in hexane) to give 0.50 g (90%) of
methyl 3-(2-hydroxyethyl)-4-propylbenzoate (33b): 1H NMR
(CDCl3) δ 1.0 (t, 3H, J ) 6.8 Hz), 1.47 (t, 1H, J ) 5.8 Hz,
exchangeable with D2O), 1.64 (sext, 2H, J ) 7.7 Hz), 2.67 (t,
2H, J ) 7.6 Hz), 2.95 (t, 2H, J ) 6.9 Hz), 3.9 (s, 3H), 3.86 (q,
2H, J ) 6.8 Hz), 7.24 (d, 1H, J ) 8.3 H), 7.7-7.9 (m, 2H).
Gen er a l P r oced u r e Y. Hyd r olysis: 3-[2-(3-Ca r boxy-6-
m eth ylp h en yl)eth yl]cofor m ycin Aglycon (43a ). According
to the procedure previously described3 3-[2-(3-carbethoxy-6-
methylphenyl)ethyl]coformycin aglycon (45f) (1.0 g, 2.9 mmol)
was hydrolyzed with 0.1 N NaOH (35 mL, 3.5 mmol) in 20
mL of dioxane. The product was isolated with DOWEX-18-
400 acetate ion-exchange resin to provide 0.8 g (88%) of 3-[2-
(3-carboxy-6-methylphenyl)ethyl]coformycin aglycon (43a ) as
1
a white powder: mp 160-170 °C dec; H NMR (DMSO-d6) δ
2.3 (s, 3H), 3.0 (t, 2H, J ) 7.3 Hz), 3.2 (br s, 2H), 4.1 (t, 2H, J
) 7.3 Hz), 4.8 (t, 1H, J ) 2.6 Hz), 7.03 (d, 1H, J ) 4.4 Hz), 7.2
(s, 1H), 7.23 (d, 1H, J ) 7.8 Hz), 7.52 (m, 1H), 7.6 (m, 2H).
Anal. (C16H18N4O3‚0.1CH3CO2H‚2.0H2O) C, H, N.
Ack n ow led gm en t. We thank Mr. Patrick McCur-
ley, Mr. Colin Ingraham, and Dr. Ken Takabayashi for
their scientific contributions, and we are grateful to Dr.
Harry Gruber for his valuable suggestions.
Gen er a l P r oced u r e U. Ar yla tion Usin g P d Ca ta lyst:
3-(3-p -F lu or op h en yl-5-ca r b et h oxyp h en et h yl)cofor m y-
cin Aglycon (41c). A suspension of 3-(3-bromo-5-carbethox-
yphenethyl)coformycin aglycon (40) (0.4 g, 0.98 mmol), p-flu-
orophenylboronic acid (0.36 g, 2.9 mmol), Pd(PPh3)4 (0.11 g,
0.1 mmol), saturated Na2CO3 (3.0 mL) and ethanol (1.0 mL)
in 20 mL of diglyme was heated at 95 °C for 1.5 h. The solvent
was evaporated under reduced pressure and azeotroped with
ethanol (2 × 10 mL). The residue was taken into 15 mL of
50% methanol in CH2Cl2, SiO2 (2.0 g) was added, and the
solvent was removed. The powder was applied to the top of a
column and eluted with 12% methanol in CH2Cl2 to give 0.2 g
(50%) of 3-(3-p-fluorophenyl-5-carbethoxyphenethyl)coformycin
aglycon (41c): 1H NMR (DMSO-d6) δ 1.33 (t, 3H, J ) 7.2 Hz),
3.1 (m, 4H), 4.17 (t, 2H, J ) 7.0 Hz), 4.33 (q, 2H, J ) 7.1 Hz),
4.8 (m, 1H), 4.92 (d, 1H, J ) 5.1 Hz), 6.9 (d, 1H, J ) 4.3 Hz),
7.17 (s, 1H), 7.2-7.8 (m, 7H), 7.99 (br s, 1H).
Su p p or tin g In for m a tion Ava ila ble: Elemental analysis
data for the final acids (Table 1) and final esters (Table 2) and
1H NMR data of the key intermediates and electrophiles. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Refer en ces
(1) Adenosine as cardio- and neuroprotective agent, see references:
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in Brain Adenosine during Bicuculline-Induced Seizure in Rats.
Circ. Res. 1980, 47, 568-577. (b) Gruber, H. E.; Hoffer, M. E.;
McAllister, D. R.; Laikind, P. K.; Lane, T. A.; Schmid-Schoen-
bein, G. W.; Engler, R. L. Increased Adenosine Concentration
in Blood from Ischemic Myocardium by AICA Riboside. Circula-
tion 1989, 80, 1400. (c) Erion, M. D. Adenosine Receptors as
Pharmacological Targets. Annu. Rep. Med. Chem. 1993, 28, 295-
304.
(2) Erion, M. D.; Kasibhatla, S. R.; Bookser, B. C.; van Poelje, P.
D.; Reddy, M. R.; Gruber, H. E.; Appleman, J . R. Discovery of
AMP Mimetics that Exhibit High Inhibitory Potency and
Specificity for AMP Deaminase. J . Am. Chem. Soc. 1999, 121,
308-319.
P r oced u r e V. TBDMS Dep r otection Usin g TBAF : 3-(2-
Hyd r oxym eth yl-5-ca r beth oxyp h en eth yl)cofor m ycin Ag-
lycon (41e). To a solution of 3-(2-(tert-butyldimethylsilyloxy-
methyl)-5-carbethoxyphenethyl)coformycin aglycon (40b) (0.25
g, 0.52 mmol) in 3 mL of THF was added tetrabutylammonium

1518 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 8
Kasibhatla et al.
(3) Bookser, B. C.; Kasibhatla, S. R.; Appleman, J . R.; Erion, M.
D. AMP Deaminase Inhibitors. 2. Initial Discovery of a Non-
Nucleotide Transition-State Inhibitor Series. J . Med. Chem.
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(4) Chan, E.; Putt, S. R.; Showalter, H. D.; Baker, D. C. Total
Synthesis of (8R)-3- (2-Deoxy-â-D-erythro-pentofuranosyl)-3,6,7,8-
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showed weak AMPDA affinity (AMPDA Ki ) 12 µM and ADA
Ki ) 6.3 µM).
J M990448E