NoVel C12 Vinyl Ketolides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1739
concentrating, the material was purified by RP HPLC and/or SiO2
chromatography (0-5% MeOH/DCM with 0.1% triethylamine)
yielding C12 vinyl ketolide.
3H), 1.11 (d, J ) 6.9, 3H), 0.84 (d, J ) 6.9, 3H), 0.77 (t, J ) 7.2,
3H). Anal. (C43H63ClN4O10) C, H, Cl, N.
6f. Following procedure A using the C12 vinyl imidazolyl
carbamate macrolide and 4-(6-methyl-9H-purin-9-yl)butan-1-amine
yielded 6f (10% yield) as a white solid. MS (ESI): 814.0 (MH+).
6a. Following procedure A using the C12 vinyl imidazolyl
carbamate macrolide and 4-imidazo[4,5-b]pyridin-1-yl-butylamine
yielded 6a (29% yield) as a white solid. MS (ESI): 798.0 (MH+).
HPLC: method 1; tR ) 12.36 min. 1H NMR (CDCl3): δ 8.55 (dd,
J ) 4.8, 1.2, 1H), 8.16 (s, 1H), 7.80 (dd, J ) 8.4, 1.5, 1H,) 7.22
(dd, J ) 8.1, 4.8, 1H), 5.95 (dd, J ) 16.8, 10.8, 1H), 5.71 (dd, J
) 17.1, 1.5, 1H), 5.55 (dd, J ) 11.1,1.5, 1H), 4.95 (dd, J ) 10.5,
2.4, 1H), 4.32 (d, J ) 7.2, 1H), 4.21-4.26 (m, 3H), 3.89 (q, J )
6.9, 1H), 3.60-3.82 (m, 2H), 3.71 (s, 1H), 3.5-3.62 (m, 1H), 3.31
(dd, J ) 9.9, 7.2, 1H), 3.06-3.16 (m, 2H), 2.59 (s, 3H), 2.52-
2.58 (m, 1H), 2.47 (s, 6H), 1.42-1.94 (m, 12H), 1.37 (d, J ) 6.9,
3H), 1.33 (s, 3H), 1.31 (d, J ) 7.5, 3H), 1.27 (d, J ) 6.0, 3H),
1.10 (d, J ) 6.9, 3H), 0.84 (d, J ) 6.9, 3H), 0.77 (t, J ) 7.5, 3H).
Anal. (C42H63N5O10*1.0H2O) C, H, N.
6b. Following procedure A using the C12 vinyl imidazolyl
carbamate macrolide and 4-imidazo[4,5-b]pyridin-3-yl-butylamine
yielded 6b (69% yield) as a white solid. MS (ESI): 798.0 (MH+).
HPLC: method 1; tR ) 12.84 min. 1H NMR (CDCl3): δ 8.38 (dd,
J ) 4.8, 1.2, 1H), 8.11 (s, 1H), 8.06 (dd, J ) 8.1, 1.2, 1H) 7.22
(dd, J ) 8.1, 4.8, 1H), 5.95 (dd, J ) 16.8, 10.8, 1H), 5.71 (dd, J
) 17.1, 1.5, 1H), 5.55 (dd, J ) 11.1,1.5, 1H), 4.95 (dd, J ) 10.5,
2.4, 1H), 4.21-4.42 (m, 4H), 3.87 (q, J ) 6.9, 1H), 3.52-3.76
(m, 2H), 3.72 (s, 1H), 3.5-3.62 (m, 1H), 3.29 (dd, J ) 10.2, 7.2,
1H), 3.02-3.16 (m, 2H), 2.60 (s, 3H), 2.52-2.58 (m, 1H), 2.44
(s, 6H), 1.42-2.04 (m, 12H), 1.36 (d, J ) 6.9, 3H), 1.33 (s, 3H),
1.31 (d, J ) 7.8, 3H), 1.27 (d, J ) 6.3, 3H), 1.11 (d, J ) 7.2, 3H),
0.84 (d, J ) 6.9, 3H), 0.80 (t, J ) 7.5, 3H). (C42H63N5O10*1.8H2O)
C, H, N.
6c. Following procedure A using the C12 vinyl imidazolyl
carbamate macrolide and 4-imidazo[4,5-b]pyridin-1-yl-4-methyl-
pentylamine yielded 6c (16% yield) as a white solid. MS (ESI):
826.0 (MH+). HPLC: method 1; tR ) 13.05 min. 1H NMR
(CDCl3): δ 8.54 (dd, J ) 4.5, 1.2, 1H), 8.23 (s, 1H), 7.97 (dd, J
) 8.1, 1.5, 1H) 7.19 (dd, J ) 8.4, 4.8, 1H), 5.92 (dd, J ) 16.8,
10.8, 1H), 5.68 (dd, J ) 17.1, 1.2, 1H), 5.54 (dd, J ) 11.1,1.2,
1H), 4.90 (dd, J ) 10.5, 2.4, 1H), 4.32 (d, J ) 7.2, 1H), 4.21 (d,
J ) 9.0, 1H), 3.89 (q, J ) 6.6, 1H), 3.63 (s, 1H), 3.44-3.62 (m,
3H), 3.32 (dd, J ) 10.2, 7.5, 1H), 2.97-3.16 (m, 2H), 2.52-2.58
(m, 1H), 2.47 (s, 6H), 2.44 (s, 3H), 2.08 (t, J ) 8.4, 2H), 1.78-
1.84 (m, 6H), 1.75 (s, 3H), 1.73 (s, 3H), 1.41-1.58 (m, 4H), 1.37
(d, J ) 6.9, 3H), 1.28-1.31 (m, 9H), 1.10 (d, J ) 6.9, 3H), 0.77-
0.82 (m, 6H). Anal. (C44H67N5O10*0.9 H2O) C, H, N.
1
HPLC: method 1; tR ) 12.47 min. H NMR (CDCl3): δ 8.81 (s,
1H) 8.07 (s, 1H), 5.94 (dd, J ) 17.4, 11.1, 1H), 5.70 (dd, J )
17.1, 1.2, 1H), 5.55 (dd, J ) 11.1,1.2, 1H), 4.91 (dd, J ) 10.8,
2.4, 1H), 4.21-4.39 (m, 4H), 3.85 (q, J ) 6.9, 1H), 3.54-3.78
(m, 3H), 3.68 (s, 1H), 3.36 (dd, J ) 9.9, 7.2, 1H), 3.01-3.11 (m,
2H), 2.87 (s, 3H), 2.80-2.86 (m, 1H), 2.54 (s, 6H), 1.38-2.00
(m, 12H), 1.34 (d, J ) 6.9, 3H), 1.27-1.31 (m, 12H), 1.11 (d, J )
6.9, 3H), 0.84 (d, J ) 6.9, 3H), 0.79 (t, J ) 7.5, 3H). Anal.
(C42H64N6O10‚2.4H2O) C, H, N.
6g. Following procedure A using the C12 vinyl imidazolyl
carbamate macrolide and 1-(4-aminobutyl)indole-4-ylamine yielded
6g (11% yield) as a white solid. MS (ESI): 812.0 (MH+). HPLC:
method 2; tR ) 6.66 min. 1H NMR (CDCl3): δ 1H NMR (CDCl3):
δ 7.01 (d, J ) 3.2, 1H), 6.97 (d, J ) 7.6, 1H), 6.80 (d, J ) 8.3,
1H), 6.37 (d, J ) 0.9, 1H), 6.35 (d, J ) 3.2, 1H), 5.94 (dd, J )
17.3, 11.0, 1H), 5.70 (dd, J ) 17.1, 1.46, 1H), 5.54 (dd, J ) 11.0,
1.465, 1H), 4.98 (dd, J ) 10.74, 2.44, 1H), 4.27 (m, 2H), 4.10 (m,
2H), 3.89 (q, J - 6.34, 1H), 3.74 (s, 1H), 3.47-3.71 (m, 3H), 3.05-
3.21 (m, 2H), 2.62 (s, 3H), 2.41-2.61 (m, 2H), 2.26 (s, 6H), 1.49-
1.85 (m, 4H), 1.21-1.47 (m, 15H), 1.34 (s, 3H), 1.24 (d, J ) 6.1,
3H), 1.09 (d, J ) 6.84, 3H), 0.78-0.85 (m, 6H). Anal. (C44H66N4O10‚
0.7H2O) C, H, N.
6h. Following procedure A using the C12 vinyl imidazolyl
carbamate macrolide and 4-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-
1-yl)butan-1-amine yielded 6h (25% yield) as a white solid. MS
(ESI): 828.0 (MH+). 1H NMR (CDCl3): δ 7.58 (d, J ) 8.7, 1H),
7.21 (d, J ) 2.7, 1H), 6.57 (d, J ) 8.7, 1H), 6.49 (d, J ) 3.0, 1H),
5.95 (dd, J ) 17.4, 11.1, 1H), 5.70 (dd, J ) 17.1, 1.2, 1H), 5.55
(dd, J ) 11.1,1.2, 1H), 4.94 (dd, J ) 10.8, 2.4, 1H), 4.31 (d, J )
7.2, 1H), 4.24 (d, J ) 9.0, 1H), 4.10 (t, J ) 7.5, 2H), 3.99 (s, 3H),
3.88 (q, J ) 6.9, 1H), 3.54-3.78 (m, 3H), 3.71 (s, 1H), 3.31 (dd,
J ) 9.9, 7.2, 1H), 3.03-3.13 (m, 2H), 2.67-2.82 (m, 1H), 2.59 (s,
3H), 2.46 (s, 6H), 1.41-1.87 (m, 12H), 1.37 (d, J ) 6.9, 3H), 1.32
(s, 3H), 1.30 (d, J ) 6.9, 3H), 1.27 (d, J ) 6.0, 3H), 1.10 (d, J )
6.9, 3H), 0.84 (d, J ) 6.6, 3H), 0.77 (t, J ) 7.5, 3H). Anal.
(C44H66N4O11‚1.3H2O) C, H, N.
6i. Following procedure A using the C12 vinyl imidazolyl
carbamate macrolide and 4-(4-(3-pyridyl)imidazolyl)butylamine
yielded 6i (39% yield) as a white solid. MS (ESI): 824.1 (MH+).
1
HPLC: method 1; tR ) 11.75 min. H NMR (CDCl3): δ 8.96 (d,
6d. Following procedure A using the C12 vinyl imidazolyl
carbamate macrolide and 4-pyrrolo[3,2-b]pyridinylbutylamine yielded
6d (37% yield) as a white solid. MS (ESI): 798.0 (MH+). HPLC:
method 1; tR ) 12.96 min. 1H NMR (CDCl3): δ 8.42 (dd, J ) 4.8,
1.2, 1H), 7.68 (d, J ) 8.1, 1H), 7.36 (d, J ) 3.3, 1H) 7.08 (dd, J
) 8.4, 4.5, 1H), 6.67 (d, J ) 4.2, 1H), 5.95 (dd, J ) 16.8, 10.8,
1H), 5.71 (dd, J ) 17.1, 1.5, 1H), 5.55 (dd, J ) 11.1,1.5, 1H),
4.95 (dd, J ) 10.5, 2.4, 1H), 4.28 (d, J ) 7.2, 1H), 4.24 (d, 9.0,
1H), 4.16 (t, J ) 7.5, 2H), 3.89 (q, J ) 6.9, 1H), 3.50-3.80 (m,
3H), 3.72 (s, 1H), 3.32 (dd, J ) 10.2, 7.2, 1H), 3.03-3.13 (m,
2H), 2.59 (s, 3H), 2.45-2.55 (m, 1H), 2.30 (s, 6H), 1.42-1.94
(m, 12H), 1.38 (d, J ) 6.9, 3H), 1.33 (s, 3H), 1.31 (d, J ) 7.5,
3H), 1.25 (d, J ) 6.0, 3H), 1.10 (d, J ) 6.9, 3H), 0.84 (d, J ) 6.9,
3H), 0.78 (t, J ) 7.2, 3H). Anal. (C43H64N4O10) C, H, N.
6e. Following procedure A using the C12 vinyl imidazolyl
carbamate macrolide and 4-(3-chloropyrrolo[3,2-b]pyridinyl)but-
ylamine yielded 6e (37% yield) as a white solid. MS (ESI): 798.0
J ) 2.1, 1H), 8.44 (dd, J ) 4.8, 1.5, 1H), 8.08 (dt, J ) 7.8, 1.8,
1H), 7.54 (d, J ) 1.2, 1H) 7.34 (d, J ) 0.9, 1H), 7.29 (m, 1H),
5.95 (dd, J ) 16.8, 10.8, 1H), 5.71 (dd, J ) 17.1, 1.5, 1H), 5.55
(dd, J ) 11.1,1.5, 1H), 4.95 (dd, J ) 10.5, 2.4, 1H), 4.28 (d, J )
7.2, 1H), 4.23 (d, J ) 9.0, 1H), 4.01 (t, J ) 7.2, 2H), 3.89 (q, J )
6.9, 1H), 3.60-3.80 (m, 2H,), 3.71 (s, 1H), 3.5-3.62 (m, 1H), 3.22
(dd, J ) 10.2, 7.2, 1H), 3.06-3.16 (m, 2H), 2.61 (s, 3H), 2.55-
2.58 (m, 1H), 2.35 (s, 6H), 1.42-1.94 (m, 12H), 1.37 (d, J ) 6.9,
3H), 1.32 (s, 3H), 1.31 (d, J ) 7.5, 3H), 1.25 (d, J ) 6.0, 3H),
1.10 (d, J ) 6.9, 3H), 0.84 (d, J ) 6.9, 3H), 0.78 (t, J ) 7.5, 3H).
Anal. (C44H65N5O10‚1.5H2O) C, H, N.
6j. Following procedure A using the C12 vinyl imidazolyl
carbamate macrolide and 4-[4-(6-methyl-pyridin-3-yl)-imidazol-1-
yl]-butylamine yielded 6j (39% yield) as a white solid. MS (ESI):
838.1 (MH+). HPLC: method 1; tR ) 11.69 min. 1H NMR
(CDCl3): δ 8.83 (d, J ) 1.8, 1H), 7.97 (dd, J ) 7.8, 2.1, 1H), 7.53
(d, J ) 1.2, 1H) 7.27 (d, J ) 1.2, 1H), 7.15 (d, J ) 8.1, 1H), 5.95
(dd, J ) 16.8, 10.8, 1H), 5.71 (dd, J ) 17.1, 1.5, 1H), 5.55 (dd, J
) 11.1,1.5, 1H), 4.95 (dd, J ) 10.5, 2.4, 1H), 4.28 (d, J ) 7.2,
1H), 4.23 (d, J ) 9.0, 1H), 4.0 (t, J ) 7.2, 2H), 3.89 (q, J ) 6.9,
1H), 3.62-3.78 (m, 2H), 3.71 (s, 1H), 3.5-3.62 (m, 1H), 3.22 (dd,
J ) 9.9, 7.2, 1H), 3.06-3.16 (m, 2H), 2.61 (s, 3H), 2.55-2.58 (m,
1H) 2.55 (s, 3H), 2.35 (s, 6H), 1.54-1.93 (m, 12H), 1.36 (d, J )
6.9, 3H), 1.33 (s, 3H), 1.31 (d, J ) 7.5, 3H), 1.25 (s, J ) 6.3, 3H),
1.10 (d, J ) 6.9, 3H), 0.84 (d, J ) 6.9, 3H), 0.79 (t, J ) 7.2, 3H).
Anal. (C45H67N5O10) C, H, N.
1
(MH+). HPLC: method 1; tR ) 13.39 min. H NMR (CDCl3): δ
8.51 (dd, J ) 4.8, 1.2, 1H), 7.69 (dd, J ) 8.4, 1.2, 1H), 7.37 (s,
1H) 7.15 (dd, J ) 8.4, 4.8, 1H), 5.93 (dd, J ) 16.8, 10.8, 1H),
5.71 (dd, J ) 17.1, 1.5, 1H), 5.56 (dd, J ) 11.1,1.5, 1H), 4.95 (dd,
J ) 10.5, 2.4, 1H), 4.31 (d, J ) 7.5, 1H), 4.24 (d, 9.0, 1H), 4.14
(t, J ) 7.5, 2H), 3.89 (q, J ) 6.9, 1H), 3.50-3.80 (m, 3H), 3.70 (s,
1H), 3.30 (dd, J ) 10.2, 7.2, 1H), 3.03-3.13 (m, 2H), 2.66-2.78
(m, 1H), 2.58 (s, 3H), 2.45 (s, 6H), 1.42-1.94 (m, 12H), 1.38 (d,
J ) 6.9, 3H), 1.33 (s, 3H), 1.31 (d, J ) 7.5, 3H), 1.27 (d, J ) 6.0,