Flexible ER Modulators
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7 1081
(CH2))), 2.05 (m, 2H, CH2), 2.70 (m, 4H, (CH2)-N-(CH2)), 2.78
(m, 2H NCH2), 4.13 (m, 2H, OCH2), 4.20 (s, 2H, CH2), 6.49-
6.51 (d, 2H, J ) 8.52, Ar), 6.89-7.49 (m, 10H, Ar), 7.91-7.98
(d, 2H, J ) 8.56, Ar) ppm. 13C NMR (CDCl3, 76.7 MHz) δ )
7.83 (CH3), 24.40 (CH2), 25.89 (CH2), 26.10 (CH2), 27.67 (CH2),
45.63 (CH2), 55.35 (CH2), 58.09 (N(CH2), 65.67 (OCH2), 113.89-
130.19 (Ar C) ppm. IR (film) ν ) 3058.2, 2852.5, 1600.4 (Cd
the manner described for 2a above. The pure product was
isolated in 39% yield following flash chromatography (CH2-
Cl2/MeOH (90:10) (product homogeneous on TLC with Rf )
0.40; 50/10/40 CH2Cl2/MeOH/EtOAc)). HPLC tR ) 13.2, 16.2
min. 1H NMR (CDCl3, 400 MHz) δ ) 0.96 (t, 3H, J ) 7.52,
CH3), 1.51 (m, 2H, CH2), 1.75 (m, 4H, (CH2)2), 2.66 (q, 2H, J
) 7.54, CH2), 2.75 (m, 4H, N(CH2)2), 2.98 (m, 2H, NCH2), 3.95
(s, 2H, CH2), 4.14 (m, 2H, OCH2), 6.63-6.65 (d, 2H, J ) 8.56,
Ar), 6.75-7.56 (m, 10H, Ar), 8.02-8.10 (d, 2H, J ) 8.64, Ar)
ppm. 13C NMR (CDCl3, 76.7 MHz) δ ) 12.90 (CH3), 23.40
(CH2), 24.72 (CH2), 27.86 (CH2), 39.99 (CH2), 54.39 (N(CH2)2),
57.13 (CH2N), 64.64 (OCH2), 113.59-156.19 (Ar C) ppm. IR
(film) ν ) 3060.0, 2856.9, 1604.9 (CdC), 1509.1, 1494.5, 1452.9,
1379.9, 1281.5, 1177.7 cm-1. HRMS calcd 425.2718, found
425.2719.
1-Ben zyl-1-p h en yl-2-[4-(m or p h olin ylet h oxy)p h en yl]-
bu t-1-en e (4e). 4e was prepared from 8e and desoxybenzoin
in the manner described for 2a above. The pure product was
isolated in 29% yield following flash chromatography (CH2-
Cl2/MeOH (90:10) (product homogeneous on TLC with Rf )
0.58; 50/10/40 CH2Cl2/MeOH/EtOAc)). HPLC tR ) 12.6, 15.6
min. 1H NMR (CDCl3, 400 MHz) δ ) 0.99 (t, 3H, J ) 7.54,
CH3), 2.63 (m, 4H, N(CH2)2), 2.83 (t, 2H, J ) 5.52, NCH2), 2.89
(q, 2H, J ) 7.03, CH2), 3.75 (m, 4H, O(CH2)2), 3.96 (s, 2H, CH2),
4.06 (t, 2H, J ) 5.52, OCH2), 6.65-6.67 (d, 2H, J ) 8.56, Ar),
6.92-7.56 (m, 12H, Ar) ppm. 13C NMR (CDCl3, 76.7 MHz), δ
) 12.52 (CH3), 27.48 (CH2), 39.61 (CH2), 55.44 (CH2), 57.09
(NCH2), 64.92 (OCH2), 66.22 ((CH2)2O), 113.22-156.18 (Ar C)
ppm. IR (film) ν ) 3059.4, 2929.2, 1605.8 (CdC), 1509.1,
1494.4, 1453.3, 1370.4, 1282.0, 1177.3 cm-1. HRMS calcd
427.2517, found 427.2511.
1,2-Dip h en yl-2-[2-(d im eth yla m in oeth oxy)ben zyl]bu t-
1-en e (5a ). 5a was prepared from 9a and propiophenone in
the manner described for 2a above. The pure product was
isolated in 21% yield following flash chromatography (CH2-
Cl2/MeOH (95:5) (product homogeneous on TLC with Rf ) 0.50;
50/50 CH2Cl2/MeOH)). HPLC tR ) 13.2, 15.6 min. 1H NMR
(CDCl3, 400 MHz) δ ) 1.46 (t, 3H, J ) 6.86, CH3), 2.07 (s, 6H,
(CH3)2), 2.74 (m, 2H, NCH2), 3.76 (q, 2H, J ) 6.85, CH2), 3.94
(s, 2H, CH2), 4.14 (m, 2H, OCH2), 6.52-6.56 (m, 2H, Ar), 6.83-
7.54 (m, 12H, Ar) ppm. 13C NMR (CDCl3, 76.7 MHz) δ ) 14.19
(CH3), 29.68 (CH2), 38.67 (CH2), 47.43, 47.54 (N(CH3)2), 58.48
(CH2N), 60.38 (OCH2), 113.89-164.59 (Ar C) ppm. IR (film) ν
) 3120.4, 2885.6, 1603.7 (CdC), 1508.7, 1496.1, 1450.5, 1382.3,
1282.4 cm-1. HRMS calcd 385.2405, found 385.2406.
C), 1575.3, 1509.3, 1494.0, 1452.7, 1372.8, 1245.1, 1175.5 cm-1
HRMS calcd 425.2718, found 425.2719.
.
1-Ben zyl-2-p h en yl[5-(m or p h olin yleth oxy)p h en yl]bu t-
1-en e (3e). 3e was prepared from 7e and propiophenone in
the manner described for 2a above. The pure product was
isolated in 40% yield following flash chromatography (CH2-
Cl2/MeOH (90:10) (product homogeneous on TLC with Rf )
0.72; 60/40 MeOH/CH2Cl2)). HPLC tR ) 15.0, 16.2 min. 1H
NMR (CDCl3, 400 MHz) δ ) 0.98 (t, 3H, J ) 7.52, CH3), 1.73
(q, 2H, J ) 7.54, CH2), 2.84 (m, 2H, NCH2), 3.02 (m, 4H, (CH2)-
N-(CH2)), 3.61 (m, 2H, OCH2), 4.12 (m, 4H, (CH2)-O-(CH2)),
4.25 (s, 2H, CH2), 6.83-6.86 (d, 2H, J ) 8.52, Ar), 6.93-7.58
(m, 10H, Ar), 7.97-7.98 (d, 2H, J ) 8.52, Ar) ppm. 13C NMR
(CDCl3, 76.7 MHz) δ ) 7.08 (CH3), 27.23 (CH2), 44.24 (CH2),
53.11 ((CH2)-N), 53.62 (N-(CH2)), 57.25 (CH2N), 65.61 (OCH2),
66.43 (2xCH2), 113.89-130.48 (Ar C) ppm. IR (film) ν ) 3059.0,
2856.4, 1600.5 (CdC), 1510.1, 1493.3, 1453.3, 1358.2, 1247.0,
1175.3 cm-1. HRMS calcd 427.2517, found 427.2511.
1-Ben zyl-1-p h en yl-2-[4-(d im eth yla m in oeth oxy)p h en yl]-
bu t-1-en e (4a ). 4a was prepared from 8a and desoxybenzoin
in the manner described for 2a above. The pure product was
isolated in 24% yield following flash chromatography (CH2-
Cl2/MeOH (90:10) (product homogeneous on TLC with Rf )
0.13; 50/10/40 CH2Cl2/MeOH/EtOAc)). HPLC tR ) 12.0, 15.0
min. 1H NMR (CDCl3, 400 MHz) δ ) 0.99 (t, 3H, J ) 7.54,
CH3), 2.45 (s, 6H, (CH3)2), 2.63 (q, 2H, J ) 7.52, CH2), 2.86
(m, 2H, NCH2), 3.96 (s, 2H, CH2), 4.07 (m, 2H, OCH2), 6.65-
6.67 (d, 2H, J ) 8.52, Ar), 6.94-7.56 (m, 10H, Ar), 8.07-8.07
(d, 2H, J ) 9.04, Ar) ppm. 13C NMR (CDCl3, 76.7 MHz) δ )
12.52 (CH3), 27.47 (CH2), 39.59 (CH2), 44.65 (N(CH3)2), 57.20
(CH2N), 64.61 (OCH2), 113.89-156.03 (Ar C) ppm. IR (film) ν
) 3083.3, 2871.1, 1604.5 (CdC), 1508.6, 1494.3, 1452.8, 1381.1,
1282.4, 1177.3 cm-1. HRMS calcd 385.2405, found 385.2406.
1-Ben zyl-1-p h en yl-2-[4-(d ieth yla m in oeth oxy)p h en yl]-
bu t-1-en e (4b). 4b was prepared from 8b and desoxybenzoin
in the manner described for 2a above. The pure product was
isolated in 34% yield following flash chromatography (CH2-
Cl2/MeOH (80:20) (product homogeneous on TLC with Rf )
0.11; 50/10/40 CH2Cl2/MeOH/EtOAc)). HPLC tR ) 15.0, 19.2
min. 1H NMR (CDCl3, 400 MHz) δ ) 1.01 (t, 3H, J ) 7.54,
CH3), 1.14 (m, 6H, (CH3)2), 2.68 (m, 6H, CH2, N(CH2)2), 2.90
(t, 2H, J ) 6.26, CH2N), 3.98 (s, 2H, CH2), 4.03 (t, 2H, J )
6.04, OCH2), 6.66-6.68 (d, 2H, J ) 8.52, Ar), 6.94-7.31 (m,
12H, Ar) ppm. 13C NMR (CDCl3, 76.7 MHz) δ ) 11.06 (CH3),
12.54 (CH3), 27.49 (CH2), 39.16 (CH2), 47.31 (N(CH2)2), 51.12
(CH2N), 65.48 (OCH2), 113.89-156.26 (Ar C) ppm. IR (film) ν
) 3080.2, 2931.2, 1605.6 (CdC), 1508.7, 1493.6, 1453.0, 1372.6,
1283.2, 1176.4 cm-1. HRMS calcd 413.2725, found 413.2719.
1-Ben zyl-1-p h en yl-2-[4-(p yr r olid in ylet h oxy)p h en yl]-
bu t-1-en e (4c). 4c was prepared from 8c and desoxybenzoin
in the manner described for 2a above. The pure product was
isolated in 24% yield following flash chromatography (CH2-
Cl2/MeOH (85:15) (product homogeneous on TLC with Rf )
0.30; 50/10/40 CH2Cl2/MeOH/EtOAc)). HPLC tR ) 12.6, 17.6
min. 1H NMR (CDCl3, 400 MHz) δ ) 0.99 (t, 3H, J ) 7.00,
CH3), 1.95 (m, 4H, (CH2)2), 2.65 (q, 2H, J ) 7.01, CH2), 2.98
(m, 4H, N(CH2)2), 3.14 (t, 2H, J ) 5.04, NCH2), 3.96 (s, 2H,
CH2), 4.17 (t, 2H, J ) 5.26, OCH2), 6.64-6.66 (d, 2H, J ) 8.52,
Ar), 6.91-7.58 (m, 10H, Ar), 8.03-8.05 (d, 2H, J ) 8.52, Ar)
ppm. 13C NMR (CDCl3, 76.7 MHz) δ ) 12.50 (CH3), 22.86
(CH2), 22.92 (CH2), 27.46 (CH2), 39.59 (CH2), 45.05 (CH2N),
53.81, 53.93 (N(CH2)2), 64.75 (OCH2), 113.58-155.69 (Ar C)
ppm. IR (film) ν ) 3059.8, 2928.2, 1603.2 (CdC), 1509.1,
1494.6, 1451.0, 1377.5, 1277.7, 1177.5 cm-1. HRMS calcd
411.2573, found 411.2562.
1,2-Dip h en yl-2-[2-(d ieth yla m in oeth oxy)ben zyl]bu t-1-
en e (5b). 5b was prepared from 9b and propiophenone in the
manner described for 2a above. The pure product was isolated
in 40% yield following flash chromatography (CH2Cl2/MeOH
(96:4) (product homogeneous on TLC with Rf ) 0.33; 50/50 CH2-
1
Cl2/MeOH)). HPLC tR ) 13.2, 15.0 min. H NMR (CDCl3, 400
MHz) δ ) 0.86 (m 6H (CH3)2), 0.98 (t, 3H, J ) 7.52, CH3), 2.36
(s, 4H, (CH2)2), 2.66 (q, 2H, J ) 7.52, CH2), 2.76 (m, 2H, NCH2),
3.92 (s, 2H, CH2), 4.08 (m, 2H, OCH2), 6.54-6.56 (d, 2H, J )
9.00, Ar), 6.80-7.35 (m, 12H, Ar) ppm. IR (film) ν ) 3059.2,
2850.6, 1604.9 (CdC), 1509.9, 1494.2, 1454.2, 1373.2, 1283.2,
1172.4 cm-1. HRMS calcd 413.2725, found 413.2719.
1,2-Dip h en yl-2-[4-(p yr r olid in ylet h oxy)b en zyl]b u t -1-
en e (5c). 5c was prepared from 9c and propiophenone in the
manner described for 2a above. The pure product was isolated
in 19% yield following prep thin-layer chromatography (CH2-
Cl2/EtOAc/MeOH (50:40:10) (product homogeneous on TLC
with Rf ) 0.65; 50/50 CH2Cl2/MeOH)). HPLC tR ) 12.6, 14.4
min. 1H NMR (CDCl3, 400 MHz) δ ) 0.90 (t, 3H, J ) 7.28,
CH3), 2.63 (m, 4H, (CH2)2), 2.28 (q, 2H, J ) 7.04, CH2), 3.65
(m, 4H, (CH2)2), 3.78 (m, 2H, NCH2), 4.15 and 4.16 (2 x s, 2H,
CH2), 4.35 (m, 2H, OCH2), 7.25-7.47 (m, 14H, Ar) ppm. 13C
NMR (CDCl3, 76.7 MHz) δ ) 17.58 (CH3), 24.17 (CH2), 29.21
(CH2), 39.50 (CH2), 47.07 (NCH2), 63.28 (N(CH2)2), 66.36
(OCH2), 116.39-146.26 (Ar C) ppm. IR (film) ν ) 3104.7,
2973.9, 1600.4 (CdC), 1492.4, 1448.6, 1370.4, 1246.1, 1166.0
cm-1. HRMS calcd 411.2573, found 411.2562.
1-Ben zyl-1-ph en yl-2-[4-(pipyr id in yleth oxy)p h en yl]bu t-
1,2-Dip h e n yl-2-[4-(p ip yr id in yle t h oxy)b e n zyl]b u t -1-
1-en e (4d ). 4d was prepared from 8d and desoxybenzoin in
en e (5d ). 5d was prepared from 9d and propiophenone in the