Phosphonic Diamide Prodrugs
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 14 4337
6.8 Hz), 1.81 (p, 1H, J ) 6.8 Hz), 1.25-1.02 (m, 6H), 0.93 (d,
6H, J ) 6.8 Hz). Anal. (C33H41N4O6PS·0.15CH2Cl2) C, H, N.
2-Amino-4-[2-{5-(N,N′-bis((S)-1-(1-ethoxycarbonyl)propyl)-
phosphonamido)}furanyl]-5-isobutylthiazole (20). Foam. 1H
NMR (DMSO-d6): δ 6.95 (m, 3H), 6.51 (m, 1H), 4.80 (m, 2H),
4.02 (m, 4H), 3.64 (m, 2H), 2.79 (d, 2H, J ) 7.0 Hz), 1.81-1.50
(m, 5H), 1.12 (m, 6H), 0.89 (d, 6H, J ) 7.0 Hz), 0.80 (m, 6H).
Anal. (C23H37N4O6PS) C, H, N.
2-Amino-4-[2-{5-(1-ethoxycarbonyl)cyclopentyl)phosphonami-
do)}furanyl]-5-isobutylthiazole (22). Foam. 1H NMR (DMSO-d6):
δ 6.90 (m, 3H), 6.48 (m, 1H), 4.70 (d, 2H, J ) 11.0 Hz), 4.00 (q,
4H, J ) 7.0 Hz), 2.82 (d, 2H, J ) 7.0 Hz), 2.20-1.40 (m, 17H),
1.12 (t, 6H, J ) 7.0 Hz), 0.92 (d, 6H, J ) 7.0 Hz). Anal.
(C27H41N4O6PS) C, H, N.
2-Amino-4-{2-[5-(N,N′-bis(1-isobutyl)phosphonamido)]furanyl}-
5-isobutylthiazole (23). Foam. 1H NMR (CDCl3): δ 7.09 (m, 1H),
6.61 (m, 1H), 5.70 (bs, 2H), 2.83-2.53 (m, 6H), 1.87 (p, 1H, J )
6.8 Hz), 1.68 (p, 2H, J ) 6.3 Hz), 0.98 (d, 6H, J ) 6.8 Hz), 0.90
(d, 12H, J ) 6.3 Hz). Anal. (C19H33N4O2PS) C, H, N.
2-Amino-4-{2-[5-(N,N′-(1-(S)-ethoxycarbonyl)ethyl)phosphon-
amido]furanyl}-5-propylsulfanylthiazole (24). Foam. 1H NMR
(CDCl3): δ 8.20 (bs, 2H), 7.26 (m, 1H), 7.04 (m, 1H), 4.30-3.90
(m, 6H), 3.60-3.30 (m, 2H), 2.68 (t, 2H, J ) 7.4 Hz), 1.59 (m,
2H), 1.43-1.16 (m, 12H), 0.94 (t, 3H, J ) 7.4 Hz). Anal.
(C20H31N4O6PS2) C, H, N.
2-Amino-4-[2-{5-(N,N′-bis((S)-1-n-butoxycarbonyl)ethyl)phos-
phonamido)}furanyl]-5-propylsulfanylthiazole (33). Foam. 1H NMR
(DMSO-d6): δ 7.38 (bs, 2H), 6.99 (m, 2H), 4.99 (m, 2H), 3.99-3.78
(m, 6H), 2.71 (t, 2H, J ) 7.0 Hz), 1.60-0.82 (m, 25H). Anal.
(C24H39N4O6PS2) C, H, N.
2-Amino-4-[2-{5-(N,N′-bis((S)-1-isopropoxycarbonyl)ethyl)phos-
phonamido)}furanyl]-5-propylsulfanylthiazole (34). Foam. 1H NMR
(DMSO-d6): δ 7.37 (bs, 2H), 6.97 (m, 2H), 5.00-4.79 (m, 4H),
3.79 (m, 2H), 2.71 (t, 2H, J ) 7.0 Hz), 1.51 (m, 2H), 1.23-1.09
(m, 18H), 0.89 (t, 3H, J ) 7.0 Hz). Anal. (C22H35N4O6PS2) C, H,
N.
2-Amino-4-[2-{5-(N,N′-bis((S)-1-n-propoxycarbonyl)ethyl)phos-
phonamido)}furanyl]-5-propylsulfanylthiazole (35). Foam. 1H NMR
(DMSO-d6): δ 7.39 (bs, 2H), 6.96 (m, 2H), 5.00 (m, 2H), 3.99-3.78
(m, 6H), 2.70 (t, 2H, J ) 7.0 Hz), 1.60-1.42 (m, 6H), 1.25 (m,
6H), 0.97-0.78 (m, 9H). Anal. (C22H35N4O6PS2) C, H, N.
2-Amino-4-[2-{5-(N,N′-bis((S)-1-cycloheptoxycarbonyl)ethyl)phos-
phonamido)}furanyl]-5-propylsulfanylthiazole (36). Foam. 1H NMR
(DMSO-d6): δ 7.38 (bs, 2H), 6.94 (m, 2H), 5.02-4.81 (m, 4H),
3.79 (m, 2H), 2.71 (t, 2H, J ) 7.0 Hz), 1.88-1.40 (m, 18H), 1.22
(m, 6H), 0.90 (t, 3H, J ) 7.0 Hz). Anal. (C26H39N4O6PS2) C, H,
N.
2-Amino-4-{2-[5-(N,N′-bis(1-methyl-1-ethoxycarbonyl)ethyl)phos-
phonamido]furanyl}-5-methylsulfanylthiazole (37). Foam. 1H NMR
(CDCl3): δ 7.25 (m, 3H), 7.08 (m, 1H), 4.21 (q, 4H, J ) 7.2 Hz),
3.99 (d, 2H, J ) 12.2 Hz), 2.36 (s, 3H), 1.65 (s, 6H), 1.45 (s, 6H),
1.24 (t, 6H, J ) 7.2 Hz). Anal. (C20H31N4O6PS2 ·0.5H2O) C, H, N.
2-Amino-4-[2-(5-({N,N′-(1-(S)-ethoxycarbonyl)ethyl}phos-
phono)furanyl]-5-ethoxycarbonylthiazole (39). Foam. 1H NMR
(DMSO-d6): δ 7.97 (bs, 2H), 7.47 (m, 1H), 6.99 (m, 1H), 5.20-4.97
(m, 2H), 4.27-3.77 (m, 8H), 1.30-1.12 (m, 15H). Anal.
(C20H29N4O8PS) C, H, N.
2-Amino-4-[2-(5-({N,N′-(1-(S)-ethoxycarbonyl)propyl}phospho-
no)furanyl]-5-ethoxycarbonylthiazole (40). Foam. 1H NMR (DMSO-
d6): δ 7.96 (bs, 2H), 7.48 (m, 1H), 6.98 (m, 1H), 5.02-4.82 (m,
2H), 4.17 (q, 2H, J ) 7.0 Hz), 4.15-3.95 (m, 4H), 3.62 (m, 2H),
1.59 (m, 4H), 1.26-1.04 (m, 9H), 0.84-0.75 (m, 6H). Anal.
(C22H33N4O8PS) C, H, N.
2-Amino-4-[2-(5-({N,N′-(1-(S)-ethoxycarbonyl)butyl}phos-
phono)furanyl]-5-ethoxycarbonylthiazole (41). Foam. 1H NMR
(DMSO-d6): δ 7.95 (bs, 2H), 7.47 (m, 1H), 6.97 (m, 1H), 5.02-4.79
(m, 2H), 4.17 (q, 2H, J ) 7.0 Hz), 4.15-3.92 (m, 4H), 3.66 (m,
2H), 1.61-0.73 (m, 23H). Anal. (C24H37N4O8PS) C, H, N.
2-Amino-4-{2-[5-(N,N′-(1-methyl-1-ethoxycarbonyl)ethyl)-phos-
phonamido]furanyl}-5-propylsulfanylthiazole (25). Mp 110-115
1
°C. H NMR (CDCl3): δ 8.30 (bs, 2H), 7.25 (m, 1H), 7.05 (m,
1H), 4.22 (q, 4H, J ) 7.2 Hz), 3.90 (d, 2H, J ) 10.8 Hz), 2.69 (t,
2H, J ) 7.0 Hz), 1.65 (s, 6H), 1.42 (s, 6H), 1.30 (t, 6H, J ) 7.2
Hz),0.95(t,3H,J)7.0Hz).Anal.(C22H35N4O6PS2 ·0.4HCl·0.5Et2O)
C, H, N.
2-Amino-4-{2-[5-(N,N′-bis(S)-1-methoxycarbonyl-2-(tert-butoxy)-
1
ethyl)phosphonamido]furanyl}-5-isobutylthiazole (26). Foam. H
NMR (DMSO-d6): δ 7.37 (bs, 2H), 6.99 (m, 1H), 6.90 (m, 1H),
4.81 (m, 2H), 3.89 (m, 2H), 3.60-3.30 (m, 10H), 2.71 (t, 2H, J )
7.0 Hz), 1.52 (m, 2H), 1.05 (m, 18H), 0.86 (t, 3H, J ) 7.0 Hz).
Anal. (C26H43N4O8PS2) C, H, N.
2-Amino-4-[2-{5-(N,N′-bis(S)-1-ethoxycarbonyl-2-methylpropyl-
phosphonamido}furanyl]-5-isobutylthiazole (27). Foam. 1H NMR
(DMSO-d6): δ 7.39 (bs, 2H), 6.95 (m, 2H), 4.71 (m, 2H), 4.03 (m,
4H), 3.53 (m, 2H), 2.71 (t, 2H, J ) 7.0 Hz), 1.92 (m, 2H), 1.55
(m, 2H), 1.20-0.76 (m, 21H). Anal. (C24H39N4O6PS2) C, H, N.
2-Amino-4-[2-{5-(N,N′-bis(1-ethoxycarbonyl)cyclopentyl)phos-
phonamido}furanyl]-5-propylsulfanylthiazole (28). Foam. 1H NMR
(CDCl3): δ 8.37 (bs, 2H), 7.28 (m, 1H), 7.05 (m, 1H), 4.18 (q, 4H,
J ) 7.2 Hz), 3.65 (d, 2H, J ) 13.2 Hz), 2.66 (t, 2H, J ) 7.4 Hz),
2.40-1.50 (m, 18H), 1.25 (m, 6H), 0.92 (t, 3H, J ) 7.4 Hz). Anal.
(C26H39N4O6PS2) C, H, N.
2-Amino-4-[2-{5-(N,N′-bis(S)-1-ethoxycarbonyl)propylphos-
phonamido}furanyl]-5-propylsulfanylthiazole (29). Foam. 1H
NMR (DMSO-d6): δ 7.37 (bs, 2H), 6.94 (m, 2H), 4.82 (m, 2H),
4.00 (m, 4H), 3.63 (m, 2H), 2.71 (t, 2H, J ) 7.0 Hz), 1.62-0.75
(m, 21H). Anal. (C22H35N4O6PS2) C, H, N.
2-Amino-4-[2-{5-(N,N′-bis(S)-1-ethoxycarbonyl-2-methylpropyl)-
phosphonamido}furanyl]-5-ethoxycarbonylthiazole (42). Foam. 1H
NMR (DMSO-d6): δ 7.95 (bs, 2H), 7.46 (m, 1H), 6.96 (m, 1H),
4.90-4.62 (m, 2H), 4.22-3.84 (m, 6H), 3.52 (m, 2H), 1.91 (m,
2H), 1.29-0.65 (m, 21H). Anal. (C24H37N4O8PS) C, H, N.
2-Amino-4-[2-(5-({N,N′-(1-(S)-ethoxycarbonyl)cyclopentyl}phos-
phono)furanyl]-5-ethoxycarbonylthiazole (43). Foam. 1H NMR
(DMSO-d6): δ 7.97 (bs, 2H), 7.50 (m, 1H), 6.96 (m, 1H), 4.75 (d,
2H, J ) 10.6 Hz), 4.18 (q, 2H, J ) 7.0 Hz), 3.99 (q, 4H, J ) 7.0
Hz), 2.20-1.44 (m, 16H), 1.22 (t, 3H, J ) 7.0 Hz), 1.12 (t, 6H, J
) 7.0 Hz). Anal. (C26H37N4O8PS) C, H, N.
2-Amino-4-[2-{5-(N,N′-bis((S)-1-ethoxycarbonyl)butyl)phos-
phonamido)}furanyl]-5-propylsulfanylthiazole (30). Foam. 1H
NMR (DMSO-d6): δ 7.36 (bs, 2H), 6.97 (m, 2H), 4.80 (m, 2H),
3.99 (m, 4H), 3.70 (m, 2H), 2.71 (t, 2H, J ) 7.0 Hz), 1.52-0.70
(m, 25H). Anal. (C24H39N4O6PS2) C, H, N.
2-Amino-4-{2-[5-(N,N′-(1-(S)-ethoxycarbonyl)ethyl)phosphona-
1
mido]furanyl}-5-phenylthiazole (44). Foam. H NMR (CDCl3): δ
7.41 (m, 7H), 6.98 (m, 1H), 6.31 (m, 1H), 4.21-3.80 (m, 6H),
3.60-3.39 (m, 2H), 1.40-1.18 (m, 12H). Anal. (C23H29N4O6PS)
C, H, N.
2-Amino-4-[2-{5-(N,N′-bis((S)-1-ethoxycarbonyl)cyclohexa-
nylmethyl)phosphonamido)furanyl]-5-propylsulfanylthiaz-
1
2-Amino-4-{2-[5-(N,N′-(1-(S)-isopropoxycarbonyl)ethyl)phos-
phonamido]furanyl}-5-phenylthiazole (45). Foam. 1H NMR
(CDCl3): δ 7.39 (m, 7H), 6.99 (m, 1H), 6.34 (m, 1H), 5.05-4.92
(m, 2H), 4.01-3.79 (m, 2H), 3.60-3.33 (m, 2H), 1.38-1.15 (m,
18H). Anal. (C25H33N4O6PS·0.2 hexane) C, H, N.
2-Amino-4-{2-[5-(N,N′-(1-methyl-1-ethoxycarbonyl)ethyl)phos-
phonamido]-furanyl}-5-phenylthiazole (46). Foam. 1H NMR
(CDCl3): δ 7.42 (m, 7H), 6.99 (m, 1H), 6.33 (m, 1H), 4.22-4.02
(m, 6H), 1.58 (s, 6H), 1.41 (s, 6H), 1.24 (t, 6H, J ) 7.0 Hz). Anal.
(C25H33N4O6PS) C, H, N.
ole (31). Foam. H NMR (DMSO-d6): δ 7.35 (bs, 2H), 6.91 (m,
2H), 4.68 (m, 2H), 4.13-3.90 (m, 6H), 3.43 (m, 2H), 2.71 (t, 2H,
J ) 7.0 Hz), 1.71-0.82 (m, 31H). Anal. (C30H47N4O6PS2) C, H,
N.
2-Amino-4-[2-{5-(N,N′-bis((S)-1-tert-butoxycarbonyl)ethyl)phos-
phonamido)}furanyl]-5-propylsulfanylthiazole (32). Foam. 1H NMR
(DMSO-d6): δ 7.40 (bs, 2H), 6.98 (m, 2H), 4.79 (m, 2H), 3.70 (m,
2H), 2.71 (t, 2H, J ) 7.0 Hz), 1.60-1.30 (m, 20H), 1.20 (d, 6H,
J ) 7.4 Hz), 0.89 (t, 3H, J ) 7.0 Hz). Anal. (C24H39N4O6PS2) C,
H, N.