Adenosine Kinase Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 22 4757
4-Ch lor o-5-iod o-7-r-L-lyxofu r a n osylp yr r olo[2,3-d ]p yr i-
m id in e (12a ): A gen er a l m eth od for d ep r otectin g 12a -
e. A mixture of 11a (3.5 g, 6.2 mmol) and 70% TFA (60 mL)
was stirred at room temperature for 30 min and evaporated
under high vacuum. The residue was coevaporated with water
(2 × 20 mL) and treated with 5% NaHCO3 solution (30 mL),
and the resulting crude product was collected by filtration and
crystallized from boiling ethanol to provide 12a as fine needles
(m, 1H), 4.8 (m 1H), 5.1 (d, 1H, exchangeable with D2O), 5.35
(d, 1H, exchangeable with D2O), 6.0 (d, J ) 7.05 Hz, 1H), 6.7
(br s, 2H, exchangeable with D2O), 7.72 (s, 1H), 8.11 (s, 1H).
MS (CI) m/ z 377 (MH)+, 261 (base+H)+. Anal. (C11H13IN4O3)
C, H, N.
4-Am in o-5-br om o-7-(5-deoxy-r-L-lyxofu r an osyl)pyr r olo-
[2,3-d ]p yr im id in e (13e). Yield 60%: mp 219-222 °C; 1H
NMR (DMSO-d6) δ 1.16 (d, J ) 6.8 Hz, 3H), 3.88 (m, 1H), 4.46
(m, 1H), 4.75 (m, 1H), 5.1 (d, 1H, exchangeable with D2O), 5.4
(d, 1H, exchangeable with D2O), 5.97 (d, J ) 7.15 Hz, 1H),
6.6-6.8 (br s, 2H, exchangeable with D2O), 7.70 (s, 1H), 7.93
(s, 1H). Anal. (C11H13BrN4O3) C, H, N.
1
(1.7 g, 67%): mp 219-220 °C. H NMR (DMSO-d6) δ 3.6 (m,
2H), 4.1 (m, 1H), 4.4 (m, 1H), 4.7 (t, 1H, exchangeable with
D2O), 4.85 (m, 1H), 5.22 (d, 1H, exchangeable with D2O), 5.48
(d, 2H, exchangeable with D2O), 6.17 (d, J ) 7.15 Hz, 1H),
8.31 (s, 1H), 8.7 (s, 1H). Anal. (C11H12ClIN3O4) C, H, N.
5-Br om o-4-ch lor o-7-r-L-lyxofu r a n osylp yr r olo[2,3-d ]p y-
r im id in e (12b). Yield 66%: mp 220-221 °C. 1H NMR (DMSO-
d6) δ 3.6 (m, 2H), 4.15 (m, 1H), 4.4 (m, 1H), 4.65 (t, 1H,
exchangeable with D2O), 4.85 (m, 1H), 5.2 (d, 1H, exchangeable
with D2O), 5.45 (d, 1H, exchangeable with D2O), 6.19 (d, J )
7.05 Hz, 1H), 8.34 (s, 1H), 8.69 (s, 1H). Anal. (C11H12ClBrN3O4)
C, H, N.
5-P h en yl-4-N-ph en ylam in o-7-r-L-lyxofu r an osylpyr r olo-
[2,3-d ]p yr im id in e (16a ). The heterocycle 10c2 (2.86 g, 10
mmol) was glycosylated with 9a (generated from 6.08 g of 4a ,
20 mmol) by the procedure described for 11a to provide
the intermediate 5-phenyl-4-N-phenylamino-7-(2,3-O-isopro-
pylidene-R-L-lyxofuranosylpyrrolo[2,3-d]pyrimidine (14a ) (3.54
g, 62%): UV (methanol) λmax 230 nm (ꢀ 5,800), 297 nm
1
(ꢀ 18,500). H NMR (CDCl3) δ 0.07-0.8 (m 15H), 1.41 (s, 3H),
4-Ch lor o-5-iod o-7-(5-O-m eth yl-r-L-lyxofu r a n osyl)p yr -
r olo[2,3-d ]p yr im id in e (12c). Yield 72%, mp 147-148 °C. 1H
NMR (DMSO-d6) δ 3.25 (s, 3H), 3.6 (m, 2H,), 4.1 (m, 1H), 4.55
(m, 1H), 4.85 (m, 1H), 5.3 (d, 1H, exchangeable with D2O), 5.5
(d, 1H, exchangeable with D2O), 6.2 (d, J ) 7.35, 1H), 8.35 (s,
1H), 8.7 (s, 1H).
1.57 (s, 3H), 3.9 (m, 2H) 4.75 (m, 1H), 5.18 (m, 1H), 5.61 (m,
1H), 6.05 (s, 1H), 6.8-7.85 (m, 12H), 8.47 (s, 1H). This
intermediate was deprotected by using 70% TFA as described
for 12a , and the resulting product was crystallized from boiling
ethanol to furnish 16a as needles (1.9 g, 74%): mp 200-202
1
°C; H NMR (DMSO-d6) δ 3.6 (m, 2H), 4.27 (m, 1H), 4.4 (m,
1H), 4.65 (t, 1H, exchangeable with D2O), 4.9 (m, 1H), 5.11
(m, 1H, exchangeable with D2O), 5.42 (m, 1H, exchangeable
with D2O), 6.19 (d, J ) 6.85 Hz, 1H), 6.95-7.8 (m, 11H), 8.4
(s, 1H). MS (CI) m/z 419 (MH)+, 287 (base + H)+. Anal.-
(C23H22N4O4) C, H, N.
A second product 15a was isolated from the column as a
glassy solid (0.85 g, 15%). UV (methanol) λmax 233 nm (ꢀ 6500),
304 nm (ꢀ 19 000). 1H NMR (CDCl3) δ 0.06-0.85 (m 15H), 1.48
(s, 3H), 1.66 (s, 3H), 3.8 (m, 2H) 4.75 (m, 1H), 5.18 (m, 1H),
5.61 (m, 1H), 6.15 (s, 1H), 6.8-7.9 (m, 12H), 8.47 (s, 1H).
4-Ch lor o-5-iod o-7-(5-d eoxy-r-L-lyxofu r a n osyl)p yr r olo-
[2,3-d ]p yr im id in e (12d ). Yield 68%: mp 192-194 °C. 1H
NMR (DMSO-d6) δ 1.2 (d, J ) 6.6 Hz, 3H), 3.95 (m, 1H), 4.5
(m, 1H), 4.9 (m, 1H), 5.2 (d, 1H, exchangeable with D2O), 5.45
(d, 1H, exchangeable with D2O), 6.18 (d, J ) 7.35 Hz,1H), 8.32
(s, 1H), 8.69 (s, 1H). Anal. (C11H12ClIN3O3) C, H, N.
5-Br om o-4-ch lor o-7-(5-deoxy-r-L-lyxofu r an osyl)pyr r olo-
[2,3-d ]p yr im id in e (12e). Yield 59%: 1H NMR (DMSO-d6) δ
1.2 (d, J ) 6.8 Hz, 3H), 3.97 (m, 1H), 4.6 (m, 1H), 4.85 (m,
1H), 5.22 (d, 1H, exchangeable with D2O), 5.45 (d, 1H,
exchangeable with D2O), 6.19 (d, J ) 7.26 Hz, 1H), 8.35 (s,
1H), 8.71 (s, 1H). MS (CI) m/z 364 (MH)+, 366 (M + 2)+, 368
(M + 4)+, 232 (base)+, 234 (base + 2)+. Anal. (C11H12ClBrN3O3)
C, H, N.
4-N-(4-F lu or op h en yl)a m in o-5-p h en yl-7-r-L-lyxofu r a -
n osylp yr r olo[2,3- d ]p yr im id in e (16b). The heterocycle 10d 2
(3.0 g, 10 mmol) was glycosylated using 9a (generated from
6.08 g of 4a , 20 mmol) by the procedure described for 11a to
furnish 14b (3.5 g, 60%). 1H NMR (DMSO-d6) δ 0.065-0.9 (m,
15H), 1.35 (s, 3H), 1.52 (s, 3H), 3.9 (m, 2H), 4.4 (m, 1H), 5.2
(m, 1H), 5.45 (m, 1H), 6.2 (s, 1H), 7.1-7.7 (m, 11H), 8.4 (s,
1H). Deprotection of 14b with 70% TFA by the procedure
described for 12a and crystallization from boiling ethanol
provided 16b in an overall 50% yield: mp 203-204 °C; 1H
NMR (DMSO-d6) δ 3.3 (m, 2H), 4.25 (m, 1H), 4.35 (m, 1H),
4.72 (t, 1H, exchangeable with D2O), 4.9 (m, 1H), 5.0 (m, 1H,
exchangeable with D2O), 5.4 (m, 1H, exchangeable with D2O),
6.2 (d, J ) 7.18 Hz, 1H), 7.1-7.82 (m, 11H), 8.39 (s, 1H). MS
(CI) m/ z 437 (MH)+, 305 (base + H)+. Anal. (C23H21FN4O4) C,
H, N.
5-P h en yl-4-N-p h en yla m in o-7-(5-O-m eth yl-r-L-lyxofu r a -
n osyl)p yr r olo[2,3- d ]p yr im id in e (16c). The heterocycle 10c
(2.86 g; 10 mmol) was glycosylated using 9b (20 mmol) by the
procedure described for 11a to give 14c, which was deprotected
with 70% TFA. The crude product was crystallized from boiling
ethanol to give 16c in an overall 48% yield: mp 162-164 °C;
1H NMR (DMSO-d6) δ 3.25 (s, 3H), 3.55 (m, 2H), 4.15 (m, 1H),
4.6 (m, 1H), 4.95 (m, 1H), 5.2 (m, 1H, exchangeable with D2O),
5.45 (m, 1H, exchangeable with D2O), 6.21 (d, J ) 7.07 Hz,
1H), 6.95-7.82 (m, 12H), 8.42 (s, 1H). MS (CI) m/z 433 (MH)+,
287 (base + H)+. Anal. (C24H24N4O4) C, H, N.
4-Am in o-5-iod o-7-r-L-lyxofu r a n osylp yr r olo[2,3-d ]p yr i-
m id in e (13a ): Gen er a l Meth od for th e P r ep a r a tion of
13a -e. A mixture of 12a (1.6 g, 3.9 mmol) and MeOH-NH3
(saturated at -10 °C) was heated in a steel bomb for 12 h at
100-120 °C. The bomb was cooled and opened carefully, and
the ammonia was allowed to evaporate. The residue was
washed with ether (2 × 20 mL), and the resulting product was
crystallized from boiling ethanol to give 13a (1.07 g, 70%): mp
236-238 °C; 1H NMR (DMSO-d6) δ 3.55 (m, 2H), 4.1 (m, 1H),
4.4 (m, 1H), 4.6 (t, 1H, exchangeable with D2O), 4.77 (m, 1H),
5.05 (d, 1H, exchangeable with D2O), 5.4 (1H, exchangeable
with D2O), 6.06 (d, J ) 6.95 Hz, 1H), 6.68 (br s, 2H,
exchangeable with D2O), 7.75 (s, 1H), 8.1 (s, 1H). Anal. (C11H13
-
IN4O4) C, H, N. Following are the yields, melting points, and
1H NMR data for 13b-e prepared by this procedure on 3-5
mmol scales.
4-Am in o-5-br om o-7-r-L-lyxofu r a n osylp yr r olo[2,3-d ]p y-
r im id in e (13b). Yield 69%: mp 245-246 °C; 1H NMR (DMSO-
d6) δ 3.55 (m, 2H), 4.12 (m, 1H), 4.35 (m, 1H), 4.62 (t, 1H,
exchangeable with D2O), 4.7 (m, 1H), 5.1 (d, 1H, exchangeable
with D2O), 5.38 (d, 1H, exchangeable with D2O), 6.04 (d, J )
6.8 Hz, 1H), 6.65-7.0 (br s, 2H, exchangeable with D2O), 7.76
(s, 1H), 8.0 (s, 1H). Anal. (C11H13BrN4O4) C, H, N.
4-Am in o-5-iod o-7-(5-O-m et h yl-r-L-lyxofu r a n osyl)p yr -
r olo[2,3-d ]p yr im id in e (13c). Yield 50%: mp 218-219 °C; 1H
NMR (DMSO-d6) δ 3.21 (s, 3H), 3.5 (m, 2H), 4.08 (m, 1H), 4.26
(m, 1H), 4.75 (m, 1H), 5.15 (d, 1H, exchangeable with D2O),
5.4 (d, 1H, exchangeable with D2O), 6.05 (d, J ) 7.05 Hz, 1H),
6.6-6.8 (br s, 2H, exchangeable with D2O), 7.78 (s, 1H), 8.11
5-P h en yl-4-N-p h en yla m in o-7-(5-d eoxy-r-L-lyxofu r a n o-
sylp yr r olo[2,3- d ]p yr im id in e (16d ). The heterocycle 10c
(3.43 g, 12 mmol) was glycosylated using 9c (generated from
6, 4.15 g, 24 mmol) by the procedure described for 11a to
provide the intermediate 14d (3.65, 69%). 1H NMR (DMSO-
d6) δ 1.2 (d, J ) 6.9 Hz, 3H), 1.35 (s, 3H), 1.53 (s, 3H), 4.45
(m, 1H), 5.05 (m, 1H), 5.45 (m, 1H), 6.23 (s, 1H), 6.95-7.7 (m,
12H), 9.42(s, 1H). Deprotection of 14d with 70% TFA followed
by crystallization from boiling ethanol gave 16d (2.55 g, 53%
(s, 1H). MS (CI) m/z 407 (MH)+, 261 (base + H)+. Anal. (C12H15
-
IN4O4) C, H, N.
4-Am in o-5-iod o-7-(5-d eoxy-r-L-lyxofu r a n osyl)p yr r olo-
[2,3-d ]p yr im id in e (13d ). Yield 52%: mp 225-227 °C; 1H
NMR (DMSO-d6) δ 1.15 (d, J ) 6.8 Hz, 3H), 3.9 (m, 1H), 4.23
1
overall): mp 224-225 °C; H NMR (DMSO-d6) δ 1.2 (d, J )
3.9 Hz, 3H), 4.0 (m, 1H), 4.6 (m, 1H), 4.92 (m, 1H), 5.1 (d, 1H,