Adenosine Kinase Inhibitors. 1
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 15 2889
gel (25% ethyl acetate in hexanes) to provide 9a as a glassy
product (5.9 g, 42%): 1H NMR (DMSO-d6) δ 0.85 (m, 15H),
1.33 and 1.55 (2s, 6H), 3.75 (m, 2H), 4.25 (m, 1H), 4.82 (m,
1H), 5.25 (m, 1H), 6.32 (d, J ) 2.6 Hz, 1H), 8.10 (s, 1H), 8.70
(s, 1H).
4-Ch lor o-5-iod o-7-(5-d eoxy-2,3-O-isop r op ylid en e-â-D-
r ibofu r a n osyl)p yr r olo[2,3-d ]p yr im id in e (9b). Glycosyla-
tion of 3a with 8b as described for 9a gave 9b as a glassy solid
in 43% yield: 1H NMR (DMSO-d6) δ 1.27 (d, J ) 6.5 Hz, 3H),
1.31 and 1.54 (2s, 6H), 4.25 (m, 1H), 4.77 (m, 1H), 5.32 (m,
1H), 6.28 (d, J ) 2.8 Hz, 1H), 8.22 (s, 1H) and 8.72 (s, 1H).
Anal. (C14H15N3O3ClI) C, H, N, Cl, I.
4-Ch lor o-5-br om o-7-(5-d eoxy-2,3-O-isop r op ylid en e-â-D-
r ibofu r a n osyl)p yr r olo[2,3-d ]p yr im id in e (9c). Glycosyla-
tion of 3b with 8b as described for 9a gave 9c as a glassy solid
in 40% yield: 1H NMR (DMSO-d6) δ 1.29 (d, J ) 6.3 Hz, 3H),
1.33 and 1.63 (2s, 6H), 4.3 (m, 1H), 4.55 (m, 1H), 5.25 (m, 1H),
6.22 (d, J ) 3.0 Hz, 1H), 8.28 (s, 1H) and 8.72 (s, 1H). Anal.
(C14H15N3O3ClBr) C, H, N, Cl, Br.
4-Ch lor o-5-m eth yl-7-(5-d eoxy-2,3-O-isop r op ylid en e-â-
D-r ibofu r a n osyl)p yr r olo[2,3-d ]p yr im id in e (9d ). Glycosy-
lation of 4a 28 with 8b as described for 9a gave 9d as a glassy
solid in 38% yield: 1H NMR (DMSO-d6) δ 1.22 (d, J ) 6.5 Hz,
3H), 1.30 and 1.55 (2s, 6H), 2.42 (s, 3H), 4.17 (m, 1H), 4.83
(m, 1H), 5.27 (m, 1H), 6.25 (d, J ) 3.75 Hz, 1H), 7.69 (s, 1H),
8.62 (s, 1H).
4-Ch lor o-5-m eth ylth io-7-(5-deoxy-2,3-O-isopr opyliden eâ-
D-r ibofu r a n osyl)p yr r olo[2,3-d ]p yr im id in e (9e). Glycosy-
lation of 4b with 8b as described for 9a gave 9e as a glassy
solid in 29% yield: 1H NMR (CDCl3) δ 1.31 (d, J ) 6.4 Hz,
3H), 1.25 and 1.62 (2s, 6H), 2.5 (s, 3H), 4.32 (m, 1H), 4.68 (m,
1H), 5.25 (m, 1H), 6.19 (d, J ) 3.5 Hz, 1H), 7.3 (s, 1H), 8.65 (s,
1H).
4-Ch lor o-5-eth oxyca r bon yl-7-(5-d eoxy-2,3-O-isop r op yl-
id en e-â-D-r ibofu r a n osyl)p yr r olo[2,3-d ]p yr im id in e (9f).
Glycosylation of 4c with 8b as described for 9a gave 9f as a
glassy solid in 26% yield: 1H NMR (DMSO-d6) δ 1.45 (m, 12H),
4.35 (q, 2H), 6.21 (d, J ) 3.0 Hz, 1H), 7.28 (s, 1H), 8.08 (s,
1H).
4.10 (m, 1H), 4.85 (m, 1H), 5.37 (m, 1H), 6.28 (d, J ) 2.6 Hz,
1H), 8.19 (s, 1H), 8.72 (s, 1H).
4-Ch lor o-5-br om o-7-(5,6-d id eoxy-2,3-O-isop r op ylid en e-
â-D-a llofu r a n osyl)p yr r olo[2,3-d ]p yr im id in e (9l). Glycosy-
lation of 3b with 8f as described for 9a gave 9l as a glassy
solid in 45% yield: 1H NMR (DMSO-d6) δ 0.88 (t, J ) 5.5 Hz,
3H), 1.31 and 1.55 (2s, 6H), 1.62 (m, 2H), 3.98 (m, 1H), 4.77
(m, 1H), 5.30 (m, 1H), 6.30 (d, J ) 3.0, 1H), 8.23 (s, 1H), 8.75
(s, 1H).
4-Ch lor o-5-iod o-7-(â-D-r ibofu r a n osyl)p yr r olo[2,3-d ]p y-
r im id in e (10a ). A mixture of 9a (500 mg, 0.9 mmol) and 70%
TFA (30 mL) was stirred for 20 min at room temperature and
concentrated under high vacuum. The residue was evaporated
with water (20 mL) and the resulting solid was stirred with
aqueous NaHCO3 for 10 min. The product was collected by
filtration, washed with water and crystallized from ethanol
to give 10a as microcrystals (222 mg, 60%): mp 190-193 °C
1
(lit.21 mp 194-196 °C); H NMR (DMSO-d6) δ 3.62 (m, 2H),
3.95 (m, 1H), 4.13 (m, 1H), 4.45 (m, 1H), 5.13 (t, 1H,
exchangeable with D2O), 5.22 (d, J ) 5.4 Hz, 1H, exchangeable
with D2O), 5.44 (d, J ) 5.2 Hz,1H, exchangeable with D2O),
6.21 (d, J ) 5.9 Hz, 1H), 8.26 (s, 1H), 8.69 (s, 1H).
4-Ch lor o-5-iod o-7-(5-d eoxyâ-D-r ibofu r a n osyl)p yr r olo-
[2,3-d ]p yr im id in e (10b). Deprotection of 9b as described for
10a gave 10b as fine needles in 65% yield: mp 180-181 °C;
1H NMR (DMSO-d6) δ 1.32 (d, J ) 6.6 Hz, 3H), 3.97 (m, 2H),
4.55 (m, 1H), 5.23 (d, J ) 6.0 Hz, 1H, exchangeable with D2O),
5.45 (d, J ) 5.7 Hz, 1H, exchangeable with D2O), 6.13 (d, J )
5.8 Hz, 1H), 8.20 (s, 1H,), 8.69 (s, 1H). Anal. (C11H11ClIN3O3)
C, H, Cl, N.
4-Ch lor o-5-br om o-7-(5-deoxy-â-D-r ibofu r an osyl)pyr r olo-
[2,3-d ]p yr im id in e (10c). Deprotection of 9c as described for
10a gave 10c as fine needles in 65% yield: mp 176-178 °C;
1H NMR (DMSO-d6) δ 1.33 (d, J ) 6.5 Hz, 3H), 3.85-405 (m,
2H), 4.50 (m, 1H), 5.22 (d, J ) 5.9 Hz, 1H, exchangeable with
D2O), 5.45 (d, J ) 5.5 Hz, 1H, exchangeable with D2O), 6.15
(d, J ) 5.5 Hz, 1H), 8.22 (s, 1H), 8.72 (s, 1H). Anal. (C11H11
ClBrN3O3) C, H, Cl, N.
-
4-Ch lor o-5-m eth yl-7-(5-deoxy-â-D-r ibofu r an osyl)pyr r olo-
[2,3-d ]p yr im id in e (10d ). Deprotection of 9d as described for
10a gave 10d as microplates in 63% yield: mp 155-156 °C;
1H NMR (DMSO-d6) δ 1.28 (d, J ) 6.2 Hz, 3H), 2.42 (s, 3H),
3.95 (m, 2H), 4.32 (m, 1H), 5.05 (br s, J ) 6.2 Hz, 1H,
exchangeable with D2O), 5.55 (br s, 1H, exchangeable with
D2O), 6.15 (d, J ) 5.78 Hz, 1H), 7.68 (s, 1H), 8.58 (s, 1H). Anal.
(C12H14ClN3O3) C, H, N.
4-Ch lor o-5-m et h ylt h io-7-(5-d eoxy-â-D-r ibofu r a n osyl)-
p yr r olo[2,3-d ]p yr im id in e (10e). Deprotection of 9e as de-
scribed for 10a gave 10e as fine needles in 62% yield: mp 147-
148 °C;1H NMR (DMSO-d6) δ 1.33 (d, J ) 6.1 Hz, 3H), 2.45 (s,
3H), 3.93 (m, 2H), 4.51 (m, 1H), 5.20 (d, J ) 5.9 Hz, 1H,
exchangeable with D2O), 5.42 (d, J ) 5.8 Hz, 1H, exchangeable
with D2O), 6.15 (d, J ) 5.4 Hz), 7.82 (s, 1H), 8.65 (s, 1H). Anal.
(C12H14ClN3O3S) C, H, N, S.
4-Ch lor o-5-iod o-7-(5-a zid o-5-d eoxy-â-D-r ibofu r a n osyl)-
p yr r olo[2,3-d ]p yr im id in e (10g). Deprotection of 9g as de-
scribed for 10a gave 10g as soft needles in 60% yield: mp 171-
172 °C; 1H NMR (DMSO-d6) δ 3.55 (m, 2H), 4.15 (m, 2H), 4.56
(m, 1H), 5.28 (br s, 1H, exchangeable with D2O), 5.65 (br s,
1H, exchangeable with D2O), 6.19 (d, J ) 5.92 Hz, 1H), 8.10
(s, 1H), 8.68 (s, 1H). Anal. (C11H10ClIN6O3‚H2O) C, H, Cl, I,
N.
4-Ch lor o-5-br om o-7-(5-azido-5-deoxy-â-D-r ibofu r an osyl)-
p yr r olo[2,3-d ]p yr im id in e (10h ). Deprotection of 9h as
described for 10a gave 10h as soft needles in 58% yield: mp
156-158 °C; 1H NMR (DMSO-d6) δ 3.65 (m, 2H), 4.07 (m, 2H),
4.57 (m, 1H), 5.30 (d, J ) 5.6 Hz, 1H, exchangeable with D2O),
5.65 (d, J ) 5.2 Hz, 1H, exchangeable with D2O), 6.25 (d, J )
5.9 Hz, 1H), 8.28 (s, 1H), 8.74 (s, 1H). Anal. (C11H10BrClN6O3)
C, H, Br, Cl, N.
4-Ch lor o-5-iod o-7-(5-a zid o-5-d eoxy-2,3-O-isop r op yl-
id en e-â-D-r ib ofu r a n osyl)p yr r olo[2,3-d ]p yr im id in e (9g).
Glycosylation of 3a with 8c as described for 9a gave 9g as a
glassy solid in 28% yield: 1H NMR (DMSO-d6) δ 1.30 and 1.55
(2s, 6H), 3.53 (m, 2H), 4.29 (m, 1H), 4.92 (m, 1H), 5.36 (m,
1H), 6.29 (d, J ) 2.8 Hz, 1H), 8.21 (s, 1H), 8.70 (s, 1H).
4-Ch lor o-5-br om o-7-(5-a zid o-5-d eoxy-2,3-O-isop r op yl-
id en e-â-D-r ibofu r a n osyl)p yr r olo[2,3-d ]p yr im id in e (9h ).
Glycosylation of 3b with 8c as described for 9a gave 9h as a
glassy solid in 25% yield: 1H NMR (CDCl3) δ 1.40 and 1.65
(2s, 6H), 3.65 (m, 2H), 4.37 (m, 1H), 4. 95 (m, 1H), 5.23 (m,
1H), 6.31 (d, J ) 2.9 Hz, 1H), 7.49 (s, 1H), 8.29 (s, 1H); IR
(KBr) 2210 cm-1
.
4-Ch lor o-5-iod o-7-(5-O-m eth yl-2,3-O-isop r op ylid en e-â-
D-r ibofu r a n osyl)p yr r olo[2,3-d ]p yr im id in e (9i). The chloro
sugar 8d was prepared from 7c as described for 8b and used
immediately in the glycosylation of 3a as described for 9a to
give 9i as a glassy solid in 32% yield: 1H NMR (DMSO-d6) δ
1.25 and 1.50 (2s, 6H), 3.33 (s, 3H) 3.55 (m, 2H), 4.35 (m, 1H),
4.83 (m, 1H), 5.28 (m, 1H), 6.32 (d, J ) 2.95 Hz, 1H), 8.11 (s,
1H), 8.7 (s, 1H).
4-Ch lor o-5-iod o-7-(5,6-d id eh yd r o-5,6-d id eoxy-2,3-O-iso-
p r op ylid e n e -â-D -a llofu r a n osyl)p yr r olo[2,3-d ]p yr im i-
d in e (9j). The chloro sugar 8e was prepared from 7d as
described for 8b and used immediately in the glycosylation of
3a as described for 9a to give 9j as a glassy solid in 45% yield:
1H NMR (DMSO-d6) δ 1.35 and 1.62 (2s, 6H), 4.56 (m, 1H),
5.10 (m, 1H), 5.19 (m, 2H), 5.36 (m, 1H), 5.93 (m, 1H), 6.38 (d,
J ) 3.3 Hz, 1H), 8.17 (s, 1H), 8.72 (s, 1H).
4-Ch lor o-5-iod o-7-(5,6-d id eoxy-2,3-O-isop r op ylid en e-â-
D-a llofu r a n osyl)p yr r olo[2,3-d ]p yr im id in e (9k ). The chloro
sugar 8f was prepared from 7e as described for 8b and used
immediately in the glycosylation of 3a as described for 9a to
give 9k as a glassy solid in 48% yield: 1H NMR (DMSO-d6) δ
0.86 (t, J ) 5.5 Hz, 3H), 1.33 and 1.55 (2s, 6H), 1.62 (m, 2H),
4-Ch lor o-5-iod o-7-(5-O-m eth yl-â-D-r ibofu r a n osyl)p yr -
r olo[2,3-d ]p yr im id in e (10i). Deprotection of 9i as described
for 10a gave 10i as microplates in 50% yield: mp 179180 °C;
1H NMR (DMSO-d6) δ 3.28 (s, 3H), 3.55 (m, 2H), 4.05 (m, 2H),