Derivatives of Histaprodifen
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5467
[2-[2-(3,3-Dip h en ylp r op yl)-1H -im id a zol-4-yl]et h yl][3-
(1H -im id a zol-4-yl)p r op yl]a m in e Tr ih yd r ogen Oxa la t e
(52) was synthesized as described from 38. The trityl-protected
intermediate was dissolved in THF without further purifica-
tion. After addition of 10 mL of 3 N HCl the solution was
refluxed overnight. THF was removed under reduced pressure,
and the residue was resolved in CH2Cl2 and extracted twice
with 1 N HCl. The aqueous phase was alkalized with NaOH
and extracted with CH2Cl2 (3 × 50 mL). The organic layer was
evaporated and the crude product purified by flash column
CHCH2), 3.74 (t, J ) 7.3 Hz, 2H, Im(C4)-CH2CH2N), 3.67 (t, J
) 7.3 Hz, 2H, N-CH2CH2-Pyr), 3.55 (t, J ) 7.3 Hz, 2H, CH2-
Pyr), 3.29 (t, J ) 7.3 Hz, 2H, Im(C4)-CH2), 3.07 (t, J ) 7.3 Hz,
2H, CH2-Im(C2)), 2.66 (q, J ) 7.7 Hz, 2H, CHCH2); +FAB-MS
(Xe, DMSO/m-NO2-benzyl-OH) m/z 411 ([M + H]+, 100), 318
(20), 306 (4), 289 (14). Anal. C, H, N.
[2-[2-(3,3-Dip h en ylp r op yl)-1H -im id a zol-4-yl]et h yl][3-
(p yr id in -3-yl)p r op yl]a m in e Dih yd r ogen Oxa la te (59) was
synthesized from 44: 1H NMR (CF3COOD) δ 8.79 (s, 1H, Pyr-
2-H), 8.75 (d, J ) 6.1 Hz, 1H, Pyr-6-H), 8.59 (d, J ) 7.9 Hz,
1H, Pyr-5-H), 8.12 (t, J ) 7.0 Hz, 1H, Pyr-4-H), 7.34-7.21 (m,
10H, 10 Ph-H), 7.18 (s, 1H, Im-5-H), 3.99 (t, J ) 7.7 Hz, 1H,
CHCH2), 3.62 (t, J ) 7.3 Hz, 2H, Im(C4)-CH2CH2N), 3.48 (t, J
1
chromatography as described above: H NMR (CF3COOD) δ
8.59 (s, 1H, Im-2-H), 7.34-7.21 (m, 11H, 10 Ph-H, Im-5-H),
7.18 (s, 1H, Im-5-H), 3.99 (t, J ) 7.7 Hz, 1H, CHCH2), 3.60 (t,
J ) 7.3 Hz, 2H, Im(C4)-CH2CH2N), 3.37 (t, J ) 7.3 Hz, 2H,
NCH2(CH2)2-Im), 3.27 (t, J ) 7.3 Hz, 2H, Im(C4)-CH2), 3.07 (t,
J ) 7.3 Hz, 2H, CH2-Im(C2)), 2.99 (s, 2H, CH2-Im), 2.66 (q, J )
7.7 Hz, 2H, CHCH2), 2.31 (m, 2H, NCH2CH2CH2-Im); +FAB-
MS (Xe, DMSO/m-NO2-benzyl-OH) m/z 414 ([M + H]+, 100),
318 (6), 307 (14), 289 (27). Anal. C, H, N.
) 7.3 Hz, 2H, NCH2(CH2)2-Pyr), 3.28 (t, J ) 7.3 Hz, 2H, Im(C4)
-
CH2), 3.10 (m, 4H, CH2-Pyr, CH2-Im(C2)), 2.66 (q, J ) 7.7 Hz,
2H, CHCH2), 2.32 (m, 2H, CH2CH2-Pyr); +FAB-MS (Xe, DMSO/
m-NO2-benzyl-OH) m/z 425 ([M + H]+, 2), 307 (17), 289 (10).
Anal. C, H, N.
[2-[2-(3,3-Dip h en ylp r op yl)-1H -im id a zol-4-yl]et h yl][4-
(p yr id in -3-yl)bu tyl]a m in e Dih yd r ogen Oxa la te (60) was
synthesized from 45: 1H NMR (CF3COOD) δ 8.71 (d, J ) 6.9
Hz, 2H, Pyr-2-H, Pyr-6-H), 8.55 (d, J ) 7.9 Hz, 1H, Pyr-5-H),
8.08 (t, J ) 7.0 Hz, 1H, Pyr-4-H), 7.34-7.21 (m, 10H, 10 Ph-
H), 7.18 (s, 1H, Im-5-H), 3.99 (t, J ) 7.7 Hz, 1H, CHCH2), 3.59
(t, J ) 7.3 Hz, 2H, Im(C4)-CH2CH2N), 3.37 (t, J ) 7.3 Hz, 2H,
NCH2(CH2)3-Pyr), 3.27 (t, J ) 7.3 Hz, 2H, Im(C4)-CH2), 3.09-
3.01 (m, 4H, CH2-Pyr, CH2-Im(C2)), 2.66 (q, J ) 7.7 Hz, 2H,
CHCH2), 1.99 (m, 2H, NCH2CH2(CH2)2-Pyr), 1.91 (m, 2H, CH2-
CH2-Pyr); +FAB-MS (Xe, DMSO/m-NO2-benzyl-OH) m/z 439
([M + H]+, 20), 307 (17), 289 (11). Anal. C, H, N.
[2-[2-(3,3-Dip h en ylp r op yl)-1H -im id a zol-4-yl]et h yl][5-
(p yr id in -3-yl)p en tyl]a m in e Dih yd r ogen Oxa la te (61) was
synthesized from 46: 1H NMR (CF3COOD) δ 8.69 (d, J ) 6.9
Hz, 2H, Pyr-2-H, Pyr-6-H), 8.55(d, J ) 8.0 Hz, 1H, Pyr-5-H),
8.08 (t, J ) 7.0 Hz, 1H, Pyr-4-H), 7.34-7.21 (m, 10H, 10 Ph-
H), 7.18 (s, 1H, Im-5-H), 3.99 (t, J ) 7.7 Hz, 1H, CHCH2), 3.57
(t, J ) 7.3 Hz, 2H, Im(C4)-CH2CH2N), 3.30 (m, 4H, NCH2(CH2)4-
Pyr, Im(C4)-CH2), 3.07 (t, J ) 7.3 Hz, 2H, CH2-Im(C2)), 2.99 (t,
J ) 7.7 Hz, 2H, CH2-Pyr), 2.66 (q, J ) 7.7 Hz, 2H, CHCH2),
1.88 (m, 4H, NCH2CH2(CH2)3-Pyr, CH2CH2-Pyr), 1.60 (m, 2H,
N(CH2)2CH2(CH2)2-Pyr); +FAB-MS (Xe, DMSO/m-NO2-benzyl-
OH) m/z 453 ([M + H]+, 6), 307 (12), 289 (8). Anal. C, H, N.
[2-[2-(3,3-Dip h en ylp r op yl)-1H -im id a zol-4-yl]et h yl][4-
(1H-im id a zol-4-yl)bu tyl]a m in e Tr ih yd r ogen Oxa la te (53)
was synthesized, deprotected, and purified as described for 52,
from 39: 1H NMR (CF3COOD) δ 8.56 (s, 1H, Im-2-H), 7.54 (s,
1H, Im-5-H), 7.34-7.21 (m, 10H, 10 Ph-H), 7.18 (s, 1H, Im-
5-H), 3.99 (t, J ) 7.7 Hz, 1H, CHCH2), 3.59 (t, J ) 7.3 Hz, 2H,
Im(C4)-CH2CH2N), 3.37 (t, J ) 7.3 Hz, 2H, NCH2(CH2)3-Im),
3.27 (t, J ) 7.3 Hz, 2H, Im(C4)-CH2), 3.07 (t, J ) 7.3 Hz, 2H,
CH2-Im(C2)), 2.90 (s, 2H, CH2-Im), 2.66 (q, J ) 7.7 Hz, 2H,
CHCH2), 1.91 (m, 4H, NCH2CH2(CH2)2-Im, CH2CH2-Im);
+FAB-MS (Xe, DMSO/ m-NO2-benzyl-OH) m/z 428 ([M + H]+,
9), 307 (1), 289 (3). Anal. C, H, N.
[2-[2-(3,3-Dip h en ylp r op yl)-1H -im id a zol-4-yl]et h yl][3-
(p yr id in -2-yl)p r op yl]a m in e Dih yd r ogen Oxa la te (55) was
synthesized as described from 40: 1H NMR (CF3COOD) δ 8.70
(d, J ) 5.8 Hz, 1H, Pyr-6-H), 8.62 (d, J ) 8.0 Hz, 1H, Pyr-3-
H), 8.01 (t, J ) 7.5 Hz, 2H, Pyr-5-H, Pyr-4-H), 7.34-7.22 (m,
10H, 10 Ph-H), 7.18 (s, 1H, Im-5-H), 3.99 (t, J ) 7.7 Hz, 1H,
CHCH2), 3.62 (t, J ) 7.3 Hz, 2H, Im(C4)-CH2CH2N), 3.52 (t, J
) 7.3 Hz, 2H, NCH2(CH2)2-Pyr), 3.35 (t, J ) 7.9 Hz, 2H, CH2-
Pyr), 3.27 (t, J ) 7.3 Hz, 2H, Im(C4)-CH2), 3.07 (t, J ) 7.3 Hz,
2H, CH2-Im(C2)), 2.66 (q, J ) 7.7 Hz, 2H, CHCH2), 2.45 (m,
2H, CH2CH2-Pyr); +FAB-MS (Xe, DMSO/m-NO2-benzyl-OH)
m/z 425 ([M + H]+, 2), 307 (16), 289 (9). Anal. C, H, N.
[2-[2-(3,3-Dip h en ylp r op yl)-1H -im id a zol-4-yl]et h yl][4-
(p yr id in -2-yl)bu tyl]a m in e Dih yd r ogen Oxa la te (56) was
synthesized from 41: 1H NMR (CF3COOD) δ 8.70 (d, J ) 5.8
Hz, 1H, Pyr-6-H), 8.62 (d, J ) 8.0 Hz, 1H, Pyr-3-H), 7.99 (t, J
) 7.6 Hz, 2H, Pyr-4-H, Pyr-5-H), 7.34-7.21 (m, 10H, 10 Ph-
H), 7.18 (s, 1H, Im-5-H), 3.99 (t, J ) 7.7 Hz, 1H, CHCH2), 3.59
(t, J ) 7.3 Hz, 2H, Im(C4)-CH2CH2N), 3.38 (t, J ) 7.3 Hz, 2H,
NCH2(CH2)3-Pyr), 3.26 (m, 4H, CH2-Pyr, Im(C4)-CH2), 3.07 (t,
J ) 7.3 Hz, 2H, CH2-Im(C2)), 2.66 (q, J ) 7.7 Hz, 2H, CHCH2),
2.02 (m, 4H, N-CH2CH2(CH2)2-Pyr, N(CH2)2CH2CH2-Pyr);
+FAB-MS (Xe, DMSO/m-NO2-benzyl-OH) m/z 439 ([M + H]+,
20), 307 (14), 289 (19). Anal. C, H, N.
[2-[2-(3,3-Dip h en ylp r op yl)-1H -im id a zol-4-yl]et h yl][5-
(p yr id in -2-yl)p en tyl]a m in e Dih yd r ogen Oxa la te (57) was
synthesized from 42: 1H NMR (CF3COOD) δ 8.70 (d, J ) 5.8
Hz, 1H, Pyr-6-H), 8.62 (d, J ) 8.0 Hz, 1H, Pyr-3-H), 7.99 (t, J
) 7.6 Hz, 2H, Pyr-4-H, Pyr-5-H), 7.34-7.21 (m, 10H, 10 Ph-
H), 7.18 (s, 1H, Im-5-H), 3.99 (t, J ) 7.7 Hz, 1H, CHCH2), 3.57
(t, J ) 7.3 Hz, 2H, Im(C4)-CH2CH2N), 3.32 (t, J ) 7.3 Hz, 2H,
NCH2(CH2)4-Pyr), 3.27 (t, J ) 7.3 Hz, 2H, Im(C4)-CH2), 3.20 (t,
J ) 7.9 Hz, 2H, CH2-Pyr), 3.07 (t, J ) 7.3 Hz, 2H, CH2-Im(C2)),
2.66 (q, J ) 7.7 Hz, 2H, CHCH2), 1.96 (m, 4H, NCH2CH2(CH2)3-
Pyr, N(CH2)3CH2CH2-Pyr), 1.64 (m, 2H, N(CH2)2CH2(CH2)2-
Pyr); +FAB-MS (Xe, DMSO/m-NO2-benzyl-OH) m/z 453 ([M +
H]+, 100), 307 (20), 289 (19). Anal. C, H, N.
[2-[2-(3,3-Dip h en ylp r op yl)-1H -im id a zol-4-yl]et h yl][2-
(p yr id in -4-yl)eth yl]a m in e Dih yd r ogen Oxa la te (62) was
synthesized from 47: 1H NMR (CF3COOD) δ 8.82 (d, J ) 5.8
Hz, 2H, Pyr-2-H, Pyr-6-H), 8.10 (d, J ) 5.8 Hz, 2H, Pyr-3-H,
Pyr-5-H), 7.34-7.23 (m, 10H, 10 Ph-H), 7.18 (s, 1H, Im-5-H),
3.99 (t, J ) 7.7 Hz, 1H, CHCH2), 3.78 (t, J ) 7.6 Hz, 2H, Im(C4)
-
CH2CH2N), 3.70 (t, J ) 7.3 Hz, 2H, NCH2CH2-Pyr), 3.62 (t, J
) 7.3 Hz, 2H, CH2-Pyr), 3.31 (t, J ) 7.3 Hz, 2H, Im(C4)-CH2),
3.08 (t, J ) 7.3 Hz, 2H, CH2-Im(C2)), 2.66 (q, J ) 7.7 Hz, 2H,
CHCH2); +FAB-MS (Xe, DMSO/m-NO2-benzyl-OH) m/z 411 ([M
+ H]+, 6), 318 (5), 307 (15), 289 (10). Anal. C, H, N.
[2-[2-(3,3-Dip h en ylp r op yl)-1H -im id a zol-4-yl]et h yl][3-
(p yr id in -4-yl)p r op yl]a m in e Dih yd r ogen Oxa la te (63) was
synthesized from 48: 1H NMR (CF3COOD) δ 8.77 (d, J ) 6.0
Hz, 2H, Pyr-2-H, Pyr-6-H), 8.02 (d, J ) 6.0 Hz, 2H, Pyr-3-H,
Pyr-5-H), 7.34-7.21 (m, 10H, 10 Ph-H), 7.18 (s, 1H, Im-5-H),
3.99 (t, J ) 7.7 Hz, 1H, CHCH2), 3.62 (t, J ) 7.3 Hz, 2H, Im(C4)
-
CH2CH2N), 3.49 (t, J ) 7.3 Hz, 2H, NCH2(CH2)2-Pyr), 3.28 (t,
J ) 7.3 Hz, 2H, Im(C4)-CH2), 3.18 (t, J ) 7.9 Hz, 2H, CH2-Pyr),
3.08 (t, J ) 7.3 Hz, 2H, CH2-Im(C2)), 2.66 (q, J ) 7.7 Hz, 2H,
CHCH2), 2.35 (m, 2H, CH2CH2-Pyr); +FAB-MS (Xe, DMSO/
m-NO2-benzyl-OH) m/z 425 ([M + H]+,6), 307 (14), 289 (9).
Anal. C, H, N.
[2-[2-(3,3-Dip h en ylp r op yl)-1H -im id a zol-4-yl]et h yl][4-
(p yr id yl-4-yl)bu tyl]a m in e Dih yd r ogen Oxa la te (64) was
1
synthesized from 49; H NMR (CF3COOD) δ 8.77 (d, J ) 5.8
[2-[2-(3,3-Dip h en ylp r op yl)-1H -im id a zol-4-yl]et h yl][2-
(p yr id in -3-yl)eth yl]a m in e Dih yd r ogen Oxa la te (58) was
synthesized from 43: 1H NMR (CF3COOD) δ 8.90 (s, 1H, Pyr-
2-H), 8.81 (d, J ) 6.1 Hz, 1H, Pyr-6-H), 8.68 (d, J ) 7.9 Hz,
1H, Pyr-5-H), 8.15 (t, J ) 7.0 Hz, 1H, Pyr-4-H), 7.34-7.21 (m,
10H, 10 Ph-H), 7.18 (s, 1H, Im-5-H), 3.99 (t, J ) 7.7 Hz, 1H,
Hz, 2H, Pyr-2-H, Pyr-6-H), 8.02 (d, J ) 5.8 Hz, 2H, Pyr-3-H,
Pyr-5-H), 7.34-7.21 (m, 10H, 10 Ph-H), 7.18 (s, 1H, Im-5-H),
3.99 (t, J ) 7.7 Hz, 1H, CHCH2), 3.59 (t, J ) 7.3 Hz, 2H, Im(C4)
-
CH2CH2N), 3.37 (t, J ) 7.3 Hz, 2H, NCH2(CH2)3-Pyr), 3.27 (t,
J ) 7.3 Hz, 2H, Im(C4)-CH2), 3.09-3.01 (m, 4H, CH2-Pyr, CH2-
Im(C2)), 2.66 (q, J ) 7.7 Hz, 2H, CHCH2), 1.96 (m, 4H,