Bisphosphonates
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17 3733
6.99-7.06 (m, 3H), 4.15 (t, 2H), 3.24 (br t, 2H), 3.10-3.20 (m,
2H), 2.61 (s, 3H), 2.10-2.33 (m, 4H). 31P NMR (5% NaOD/
D2O): δ 19.00. Anal. (C13H23NO8P2) C, H, N, P.
116 °C. 1H NMR (NaOD/D2O, 200 MHz): δ 7.21-7.44 (m, 5H),
3.08 (t, 2H), 2.70-2.88 (m, 4H), 1.83-2.09 (m, 2H). 31P NMR
(5% NaOD/D2O): δ 19.01. Anal. (C11H19NO7P2S‚0.25H2O) C,
H, N, P, S.
1-Hydr oxy-3-[m eth yl-(3-(3-m eth ylph en oxy)pr opyl)am i-
n o]p r op ylid en e-1,1-bisp h osp h on ic Acid (5e). Yield: 27%;
mp 152-158 °C. H NMR (NaOD/D2O, 300 MHz): δ 7.27 (t,
1H), 6.82-6.85 (m, 3H), 4.12 (t,2 H), 2.83-2.90 (m, 2H), 2.64-
2.72 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.06-2.21 (m, 2H),
1.96-2.06 (m, 2H). 31P NMR (5% NaOD/D2O): δ 19.00. Anal.
(C14H25NO8P2) C, H, N, P.
1-Hyd r oxy-3-[m et h yl-(2-p h en ylsu lfa n ylet h yl)a m in o]-
p r op ylid en e-1,1-bisp h osp h on ic Acid (5p ). Yield: 30%; mp
170-172 °C (dec). 1H NMR (NaOD/D2O, 300 MHz): δ 7.48 (d,
2H), 7.39 (t, 2H), 7.30 (t, 1H), 3.18-3.27 (m, 2H), 2.95-3.08
(m, 4H), 2.51 (s, 3H), 2.17 (7-line system, 2H). 31P NMR (5%
NaOD/D2O): δ 18.97. Anal. (C12H21NO7P2S) C, H, N, P, S.
1
1-Hyd r oxy-3-[m eth yl-(3-(4-flu or op h en oxy)p r op yl)a m i-
n o]p r op ylid en e-1,1-bisp h osp h on ic Acid (5f). Yield: 35%;
mp 165-172 °C. H NMR (NaOD/D2O, 300 MHz): δ 7.12 (t,
2H), 6.96-7.05 (m, 2H), 4.10 (t, 2H), 2.83-2.90 (m, 2H), 2.64-
2.73 (m, 2H), 2.31 (s, 3H), 2.07-2.17 (m, 2H), 1.95-2.07 (m,2
H). 31P NMR (5% NaOD/D2O): δ 19.00. Anal. (C13H22FNO8P2‚
0.5H2O) C, H, N, F, P.
1-Hyd r oxy-3-[(3-p h en ylsu lfa n ylp r op yl)a m in o]p r op yli-
d en e-1,1-bisp h osp h on ic Acid (5q). Yield: 63%; mp 154-
156 °C. 1H NMR (NaOD/D2O, 300 MHz): δ 7.32-7.36 (m, 4H),
7.23-7.30 (m, 1H), 3.03 (t, 2H), 2.96 (t, 2H), 2.78 (t, 2H), 2.07
(7-line system, 2H), 1.83 (5-line system, 2H). 31P NMR (5%
NaOD/D2O): δ 19.02. Anal. (C12H21NO7P2S) C, H, N, P, S.
1-H yd r oxy-3-[m et h yl-(2-(4-ch lor op h en ylsu lfa n ylet h -
yl))a m in o]p r op ylid en e-1,1-bisp h osp h on ic Acid (5s).
Yield: 31%; mp 125-130 °C. 1H NMR (NaOD/D2O, 300
MHz): δ 7.07 (s, 4H), 2.67 (t, 2H), 2.34-2.46 (m, 2H), 2.21 (t,
2H), 1.84 (s, 3H), 1.64-1.80 (m, 2H), 1.48 (5-line system, 2H).
31P NMR (5% NaOD/D2O): δ 19.11 Anal. (C13H22ClNO7P2S)
C, H, Cl, N, P, S.
1
1-Hyd r oxy-3-[m eth yl-(3-(4-ch lor op h en oxy)p r op yl)a m i-
n o]p r op ylid en e-1,1-bisp h osp h on ic Acid (5g). Yield: 71%;
1
mp 155-162 °C. H NMR (NaOD/D2O, 300 MHz): δ 7.00 (d,
2H), 6.62 (d, 2H), 3.72 (t, 2H), 2.33-2.46 (m, 2H), 2.16-2.27
(m, 2H), 1.88 (s, 3H), 1.50-1.80 (m, 4H). 31P NMR (5% NaOD/
D2O): δ 19.00. Anal. (C13H21ClNO8P2) C, H, N, Cl, P.
1-Hyd r oxy-3-[m et h yl-(3-(4-m et h oxyp h en oxy)p r op yl)-
a m in o]p r op ylid en e-1,1-bisp h osp h on ic Acid (5h ). Yield:
23%; mp 127-133 °C. 1H NMR (NaOD/D2O, 300 MHz): δ 6.78
(br s, 4H), 3.86 (t, 2H), 3.69 (s, 3H), 2.62-2.62 (m, 2H), 2.33-
2.46 (m,2 H), 2.03 (s, 3H), 1.69-1.98 (m, 4H). 31P NMR (5%
NaOD/D2O): δ 19.00. Anal. (C14H25NO9P2‚0.5H2O) C, H, N,
P.
1-Hydr oxy-2-(im ida zol-2-yl)eth yliden e-1,1-bisp h osp h o-
n ic Acid (6a ). Yield: 30%; mp 235 °C (dec). 1H NMR (NaOD/
D2O, 300 MHz): δ 6.66 (s, 2H), 3.09 (t, J H-P ) 13 Hz, 2H). 31
P
NMR (5% NaOD/D2O): δ 18.78. Anal. (C5H10N2O7P2‚0.5H2O)
C, H, N, P. P: calcd, 22.04; found, 22.5.
1-Hydr oxy-2-(1-m eth ylim idazol-2-yl)eth yliden e-1,1-bis-
p h osp h on ic Acid (6b). Yield: 46%; mp 261 °C (dec). 1H NMR
(NaOD/D2O, 300 MHz): δ 6.66 (s, 1H), 6.57 (s, 1H), 3.41 (s,
3H), 2.99 (t, J H-P ) 11 Hz, 2H). 31P NMR (5% NaOD/D2O): δ
17.96. Anal. (C6H12N2O7P2‚H2O) C, H, N, P.
1-Hyd r oxy-2-(1-ben zylim id a zol-2-yl)eth ylid en e-1,1-bis-
p h osp h on ic Acid (6c). Yield: 52%; mp 171 °C (dec). 1H NMR
(NaOD/D2O, 250 MHz): δ 7.3-7.5 (m, 5H), 7.24 (br s, 1H),
7.19 (br s, 1H), 5.43 (s, 2H), 3.52 (t, J H-P ) 12 Hz, 2H). 31P
NMR (5% NaOD/D2O): δ 17.81.
1-Hydr oxy-2-(im ida zol-4-yl)eth yliden e-1,1-bisp h osp h o-
n ic Acid (6d ). Yield: 41%; mp 238-240 °C (dec). 1H NMR
(NaOD/D2O, 250 MHz): δ 7.49 (s, 1H), 6.70 (s, 1H), 3.16 (t,
J H-P ) 12 Hz, 2H). 31P NMR (5% NaOD/D2O): δ 18.98. Anal.
(C5H10N2O7P2) C, H, N, P.
1-H yd r oxy-3-[et h yl-(3-p h en oxyp r op yl)a m in o]p r op y-
lid en e-1,1-bisp h osp h on ic Acid (5i). Yield: 61%; mp 195-
1
197 °C. H NMR (NaOD/D2O, 300 MHz): δ 7.07 (t, 2H), 6.74
(t, 1H), 6.71 (d, 2H), 3.78 (t, 2H), 2.46-2.57 (m, 2H), 2.30-
2.40 (m, 2H), 2.27 (q, 2H), 1.59-1.84 (m, 4H), 0.71 (t, 3H). 31
P
NMR (5% NaOD/D2O): δ 19.16. Anal. (C14H25NO8P2) C, H, N,
P.
1-Hyd r oxy-3-[p r op yl-(3-p h en oxyp r op yl)a m in o]p r op y-
lid en e-1,1-bisp h osp h on ic Acid (5j). Yield: 50%; mp 197-
1
199 °C. H NMR (NaOD/D2O, 300 MHz): δ 7.06 (t, 2H), 6.73
(t, 1H), 6.70 (d, 2H), 3.77 (t, 2H), 2.46-2.58 (m,2 H), 2.30-
2.40 (m,2 H), 2.08-2.19 (m, 2H), 1.58-1.84 (m, 4H), 1.16 (6-
line system, 2H), 0.52 (t, 3H). 31P NMR (5% NaOD/D2O): δ
19.16. Anal. (C15H27NO8P2‚0.5H2O) C, H, N, P.
1-H yd r oxy-3-(im id a zol-4-yl)p r op ylid en e-1,1-b isp h os-
p h on ic Acid (6e). Yield: 38%; mp 249-252 °C (dec). 1H NMR
(NaOD/D2O, 300 MHz): δ 7.25 (s, 1H), 6.53 (s, 1H), 2.52-2.63
1-H yd r oxy-3-[b u t yl-(3-p h en oxyp r op yl)a m in o]p r op y-
lid en e-1,1-bisp h osp h on ic Acid (5k ). Yield: 45%; mp 181-
1
183 °C (dec). H NMR (NaOD/D2O, 300 MHz): δ 7.07 (t, 2H),
(m, 2H), 1.77-1.95 (m, 2H). 31P NMR (5% NaOD/D2O):
19.31. Anal. (C6H12N2O7P2‚0.75H2O) C, H, N, P.
δ
6.74 (t, 1H), 6.71 (d, 2H), 3.79 (t, 2H), 2.46-2.57 (m,2 H), 2.30-
2.40 (m, 2H), 2.13-2.21 (m, 2H), 1.58-1.83 (m, 4H), 1.05-
1.19 (m, 2H), 0.94 (6-line system, 2H), 0.55 (t, 3H). 31P NMR
(5% NaOD/D2O): δ 19.16. Anal. (C16H29NO8P2) C, H, N, P.
1-H yd r oxy-3-[m et h yl-(4-p h en oxyb u t yl)a m in o]p r op y-
lid en e-1,1-bisp h osp h on ic Acid (5l). Yield: 45%; mp 153-
1-Hydr oxy-2-(2-m eth ylim idazol-4-yl)eth yliden e-1,1-bis-
p h osp h on ic Acid (6f). Yield: 43%; mp 261-262 °C (dec). 1H
NMR (NaOD/D2O, 250 MHz): δ 6.38 (s, 1H), 2.96 (t, J H-P
)
12 Hz, 2H), 2.01 (s, 3H). 31P NMR (5% NaOD/D2O): δ 19.02.
Anal. (C6H12N2O7P2‚0.5H2O) C, H, N.
1
156 °C (dec). H NMR (NaOD/D2O, 250 MHz): δ 7.15 (t, 2H),
1-Hydr oxy-2-(2-ph en ylim ida zol-4-yl)eth ylid en e-1,1-bis-
p h osp h on ic Acid (6g). Yield: 30%; mp 223-224 °C (dec).
1H NMR (NaOD/D2O, 250 MHz): δ 7.45 (d, 2H), 7.10 (t, 2H),
7.02 (t, 1H), 6.58 (s, 1H), 3.05 (t, J H-P ) 12 Hz, 2H). 31P NMR
(5% NaOD/D2O): δ 19.12. Anal. (C11H14N2O7P2‚1.5H2O) C, H,
N.
1-Hydr oxy-2-(5-m eth ylim idazol-4-yl)eth yliden e-1,1-bis-
p h osp h on ic Acid (6h ). Yield: 51%; mp 217-218 °C. 1H NMR
(NaOD/D2O, 250 MHz): δ 7.26 (s, 1H), 2.99 (t, J H-P ) 12 Hz,
2H), 1.88 (s, 3H). 31P NMR (5% NaOD/D2O): δ 19.12. Anal.
(C6H12N2O7P2‚0.25H2O) C, H, N, P.
1-Hyd r oxy-2-(im id a zol-1-yl-a m in o)eth ylid en e-1,1-bis-
p h osp h on ic Acid (6i). Yield: 67%; mp 242-244 °C (dec). 1H
NMR (NaOD/D2O, 300 MHz): δ 7.80 (s, 1H), 7.30 (s, 1H), 6.95
(s, 1H), 4.50 (t, J H-P ) 10 Hz, 2H). 31P NMR (5% NaOD/D2O):
δ 16.18. Anal. (C5H10N2O7P2‚H2O) C, H, N, P.
1-Hyd r oxy-3-(im id a zol-1-yl-a m in o)p r op ylid en e-1,1-bis-
p h osp h on ic Acid (6j). Yield: 63%; mp 246-247 °C (dec). 1H
NMR (NaOD/D2O, 250 MHz): δ 7.50 (s, 1H), 7.02 (s, 1H), 6.66
(s, 1H), 4.08-4.18 (m, 2H), 2.00-2.20 (m, 2H). 31P NMR (5%
6.76-6.88 (m, 3H), 3.85 (t, 2H), 2.42-2.55 (m, 2H), 2.16-2.27
(br t, 2H), 1.96 (s, 3H), 1.70-1.90 (m, 2H), 1.30-1.60 (m, 4H).
31P NMR (5% NaOD/D2O): δ 19.01. Anal. (C14H25NO8P2) C,
H, N, P. P: calcd, 15.59; found, 14.9.
1-H yd r oxy-3-[m et h yl-(6-p h en oxyh exyl)a m in o]p r op y-
lid en e-1,1-bisp h osp h on ic Acid (5m ). Yield: 55%; mp 183-
1
187 °C (dec). H NMR (NaOD/D2O, 300 MHz): δ 7.07 (t, 2H),
6.74 (t, 1H), 6.71 (d, 2H), 3.77 (t, 2H), 2.34-2.44 (m, 2H), 2.04-
2.14 (m, 2H), 1.87 (s, 3H), 1.64-1.84 (m, 2H), 1.46 (5-line
system, 3H), 1.09-1.26 (m, 4H), 0.97-1.09 (m, 2H). 31P NMR
(5% NaOD/D2O): δ 19.14. Anal. (C16H29NO8P2) C, H, N, P.
1-Hyd r oxy-3-[m eth yl-(3-p h en oxyp r op yl)a m in o]bu tyl-
id en e-1,1-bisp h osp h on ic Acid (5n ). Yield: 72%; mp 221-
223 °C. 1H NMR (NaOD/D2O, 300 MHz): δ 7.37 (t, 2H), 6.99-
7.08 (m, 3H), 4.11 (t, 2H), 2.72-2.80 (m, 2H), 2.55-2.63 (m,
2H), 2.38 (s, 3H), 1.96-2.09 (m, 2H), 1.76-1.93 (m, 4H). 31P
NMR (5% NaOD/D2O): δ 19.37. Anal. (C14H25NO8P2‚0.5H2O)
C, H, N, P.
1-H yd r oxy-3-[(2-p h en ylsu lfa n ylet h yl)a m in o]p r op yli-
d en e-1,1-bisp h osp h on ic Acid (5o). Yield: 71%; mp 108-