2520 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Moloney et al.
505.26827, C28H35N5O4 requires M+ 505.26891. Anal. (C28H35
N5O4‚1.0H2O‚1.5CH3CO2H) C, H, N. HPLC retention time )
15.66 min.
CH3), 2.12 (6H, s, 2 × NCH3), 2.5 (2H, m, CH2NMe2 under
DMSO peak), 2.91 (2H, t, 5-CH2), 3.05 (2H, m, 3-CH2), 3.59
(2H, t, CH2Hyd), 4.5 (2H, d, CH2NHCO), 7.0 (1H, d, H6), 7.3
(2H, m, H7, H4), 7.6 (2H, d, H3′, H5′), 7.7 (2H, d, H2′, H6′),
8.1 (1H, s, NH), 9.7 (1H, m, NH), 11.2 (1H, s, NH); found M+
-
N-(2-Am in oben zyl)-5-[2-(4,4-d im eth yl-2,5-d ioxo-1-im id -
a zolid in yl)eth yl]-3-[2-(d im eth yla m in o)eth yl]-1H-in d ole-
2-ca r boxa m id e (46). Method 5: white powder; mp 201-202
°C; MS m/z 490 (M+); 1H NMR δ 1.15 (6H, s, 2 × CH3), 2.1
(6H, s, 2 × NCH3), 2.50 (2H, m, CH2NMe2), 2.9 (2H, m, 5-CH2),
3.05 (2H, m, 3-CH2), 3.62 (2H, m, CH2Hyd), 4.5 (2H, d, CH2-
NHCO), 5.1 (2H, br s, NH2), 6.5 (1H, t, ArH, J ) 7.5 Hz), 6.65
(1H, d, H6, J ) 7.5 Hz), 6.9-7.1 (2H, m, 2 × ArH), 7.3 (2H, m,
2 × ArH), 8.1 (1H, s, NH), 9.55 (1H, t, NH), 11.2 (1H, s, NH).
Anal. (C27H34N6O3‚0.5H2O) C, H, N. HPLC retention time )
12.66 min.
N-(2-Am in ob en zyl)-5-[2-(2,5-d ioxo-1-im id a zolid in yl)-
eth yl]-3-[2-(d im eth yla m in o)eth yl]-1H-in d ole-2-ca r box-
a m id e (47). Method 5: cream powder; mp 213-215 °C; MS
m/z 463 (M + 1)+; 1H NMR δ 2.1 (6H, s, 2 × NCH3), 2.92 (2H,
m, CH2NMe2), 3.05 (2H, m, 5-CH2), 3.6 (2H, m, CH2Hyd), 3.8
(2H, s NCH2CO), 4.4 (2H, d, CH2NHCO), 5.1 (2H, br s, NH2),
6.5 (1H, t, ArH, J ) 7.5 Hz), 6.65 (1H, d, H6), 7.0 (3H, m, 3 ×
ArH), 7.3 (2H, m, 2 × ArH), 7.95 (1H, s, NH), 9.6 (1H, br t,
NH), 11.2 (1H, s, NH). Anal. (C25H30N6O3‚0.6H2O) C, H, N.
HPLC retention time ) 11.3 min.
543.24599, C28H32N5O3F3 requires M+ 543.24572. Anal. (C28H32
-
N5O3F3) C, H, N. HPLC retention time ) 14.76 min.
N-(4-Bip h en ylylm eth yl)-5-[2-(4,4-d im eth yl-2,5-d ioxo-1-
im id a zolid in yl)eth yl]-3-[2-(d im eth yla m in o)eth yl]-1H-in -
d ole-2-ca r boxa m id e (40). Method 5: white powder; 49 mg
(60%); mp 142-144 °C; MS m/z 552 (M + 1)+; 1H NMR δ 1.15
(6H, s, 2 × CH3), 2.1 (6H, s, 2 × NCH3), 2.52 (2H, m, CH2-
NMe2 under DMSO peak), 2.9 (2H, t, 5-CH2, J ) 7.0 Hz), 3.05
(2H, m, 3-CH2), 3.6 (2H, t, CH2Hyd, J ) 7.0 Hz), 4.55 (2H, d,
CH2NHCO, J ) 5.0 Hz), 7.05 (1H, d, H6, J ) 7.5 Hz), 7.25-
7.5 (7H, m, H7, H4, 5 × ArH), 7.65 (4H, d, 4 × ArH, J ) 6.0
Hz), 8.1 (1H, s, NH), 9.7 (1H, br t, NH), 11.15 (1H, br s, NH).
Anal. (C33H37N5O3‚0.5H2O) C, H, N. HPLC retention time )
19.19 min.
N-(1-Na p h t h ylm et h yl)-5-[2-(4,4-d im et h yl-2,5-d ioxo-1-
im id a zolid in yl)eth yl]-3-[2-(d im eth yla m in o)eth yl]-1H-in -
d ole-2-ca r boxa m id e (41). Method 5: white powder; mp 195-
210 °C, softens; MS m/z 526 (M + 1)+; 1H NMR δ 1.15 (6H, s,
2 × CH3), 1.8 (6H, s, 2 × NCH3), 2.45 (2H, m, CH2NMe2), 2.9
(2H, m, 5-CH2), 3.0 (2H, t, 3-CH2), 3.6 (2H, t, CH2Hyd, J )
7.0 Hz), 5.0 (2H, d, CH2NHCO), 7.0 (1H, d, H6), 7.3 (2H, m,
H7, H4), 7.5-7.6 (4H, m, 4 × ArH), 7.9-8.2 (4H, m, 3 × ArH,
NH), 9.7 (1H, t, NH), 11.2 (1H, s, NH); found M+ 525.27539,
C31H35N5O3 requires M+ 525.27399. Anal. (C31H35N5O3‚0.80H2O)
C, H, N. HPLC retention time ) 17.7 min.
N-Meth oxy-5-[2-(4,4-d im eth yl-2,5-d ioxo-1-im id a zolid i-
n yl)et h yl]-3-[2-(d im et h yla m in o)et h yl]-1H -in d ole-2-ca r -
boxa m id e (48). Method 5: off-white powder; mp 148-150 °C;
1
MS m/z 416 (M + 1)+; H NMR δ 1.15 (6H, s, 2 × CH3), 2.22
(6H, s, 2 × NCH3), 2.55 (2H, m, CH2), 2.90 (2H, m, CH2NMe2),
3.05 (2H, m, 5-CH2), 3.60 (2H, m, CH2Hyd), 3.72 (3H, s, OCH3),
7.05 (1H, d, H6, J ) 7.5 Hz), 7.25-7.35 (2H, m, H7, H4),
8.1 (1H, s, NH), 11.18 (1H, s, NH); found M+ 415.22458,
N-(4-Meth ylben zyl)-5-[2-(4,4-d im eth yl-2,5-d ioxo-1-im id -
a zolid in yl)eth yl]-3-[2-(d im eth yla m in o)eth yl]-1H-in d ole-
2-ca r boxa m id e (42). Method 5: white powder; mp 206-207
C
21H29N5O4 requires M+ 415.22195. HPLC retention time )
10.11 min.
1
°C; MS m/z 490 (M + 1)+; H NMR δ 1.15 (6H, s, 2 × CH3),
N-(2-Hyd r oxyben zyl)-3-[2-(d im eth yla m in o)eth yl]-5-[2-
(4,4-dim eth yl-2,5-dioxo-1-im idazolidin yl)eth yl]-1H-in dole-
2-ca r boxa m id e (49). Method 5: white solid; mp 198-200 °C;
2.05 (6H, s, 2 × NCH3), 2.3 (3H, s, CH3), 2.9 (2H, m, CH2-
NMe2), 3.05 (2H, t, 5-CH2), 3.6 (2H, t, CH2Hyd, J ) 7.0 Hz),
4.5 (2H, d, CH2NHCO), 7.07 (1H, dd, H6, J ) 8.4 Hz), 7.2-7.4
(6H, m, H7, H4, 4 × ArH), 8.1 (1H, s, NH), 9.65 (1H, t, NH),
11.2 (1H, s, NH). Anal. (C28H35N5O3‚0.25H2O) C, H, N. HPLC
retention time ) 16.34 min.
1
MS m/z 492 (M + 1)+; H NMR δ 1.15 (6H, s, 2 × CH3), 2.1
(6H, s, 2 × NCH3), 2.9 (2H, m, CH2NMe2), 3.05 (2H, m, 5-CH2),
3.6 (2H, m, CH2Hyd), 4.4 (2H, d, CH2NHCO), 6.8 (2H, m, 2 ×
ArH), 7.0 (2H, m, 2 × ArH), 7.25 (3H, m, 3 × ArH), 8.1 (1H, s,
NH), 9.55 (1H, t, NH), 11.2 (1H, s, NH). Anal. (C27H33N5O4‚
0.25H2O‚0.5C2H5OH) C, H, N. HPLC retention time ) 12.93
min.
N-(2-Meth yla m id o)-5-[2-(4,4-d im eth yl-2,5-d ioxo-1-im id -
a zolid in yl)eth yl]-3-[2-(d im eth yla m in o)eth yl]-1H-in d ole-
2-ca r boxa m id e (43). Method 5 (using glycinamide hydro-
chloride): cream powder; MS m/z 443 (M + 1)+; 1H NMR δ
1.18 (6H, s, 2 × CH3), 2.23 (6H, s, 2 × NCH3), 2.55 (2H, m,
CH2NMe2), 2.98 (2H, m, CH2N), 3.1 (2H, m, 5-CH2), 3.55 (2H,
m, 3-CH2), 3.95 (2H, d, NHCH2), 7.08 (1H, d, H6), 7.09 (1H,
br s, NHA), 7.32 (2H, m, H7, H4), 7.42 (1H, br s, NHA′), 8.13
(1H, s, NH), 9.2 (1H, t, NHCH2), 11.2 (1H, s, NH); found M+
442.23082, C22H30N6O4 requires M+ 442.23285. HPLC reten-
tion time ) 9.98 min.
N-P h en yl-2-oxo-5-br om op en ta m id e (50). Method 6: iso-
lated as a yellow wax; MS m/z 269, 271 (M+, M + 2)+); 1H NMR
δ (CDCl3) 2.25 (2H, m, 4-CH2), 3.23 (2H, m, 5-CH2), 3.5 (2H,
m, 3-CH2), 3.65 (2H, m, CH2Hyd), 7.19 (1H, m, ArH), 7.36 (2H,
m, 2 × ArH), 7.68 (2H, m, 2 × ArH), 8.66 (1H, s, NH); found
M+ 269.00603, C11H12BrNO2 requires M+ 269.00514. HPLC
retention time ) 18.31 min.
N-P h en yl-5-[2-(4,4-dim eth yl-2,5-dioxo-1-im idazolidin yl)-
et h yl]-3-(2-a m in oet h yl)-1H -in d ole-2-ca r b oxa m id e (51).
N-(3-Am in oben zyl)-5-[2-(4,4-d im eth yl-2,5-d ioxo-1-im id -
a zolid in yl)eth yl]-3-[2-(d im eth yla m in o)eth yl]-1H-in d ole-
2-ca r boxa m id e (44). Method 5: cream powder; MS m/z 491
1
Method 9: white solid; MS m/z 434 (M + 1)+; H NMR δ 1.17
(6H, s, 2 × CH3), 2.95 (2H, m, 5-CH2), 3.05 (2H, m, 3-CH2),
3.38 (2H, m, CH2NMe2), 3.65 (2H, m, CH2Hyd), 7.11 (2H, m,
H6, ArH), 7.35 (3H, m, H7, 2 × ArH), 7.5 (1H, s, H4), 7.85
(4H, m, 2 × ArH, NH2), 8.15 (1H, s, NH), 10.5 (1H, s, NH),
12.08 (1H, s, NH); found M+ 433.21112, C24H27N5O3 requires
M+ 433.21139. HPLC retention time ) 13.69 min.
1
(M + 1)+; H NMR δ 1.15 (6H, s, 2 × CH3), 2.08 (6H, s, 2 ×
NCH3), 2.52 (2H, m, CH2NMe2, under DMSO peak), 2.9 (2H,
m, 5-CH2), 3.05 (2H, m, 3-CH2), 3.52 (2H, m, CH2Hyd), 4.36
(2H, d, CH2NHCO), 5.05 (2H, br s, NH2), 6.5 (3H, m, 3 × ArH),
7.0 (2H, m, 2 × ArH), 7.28 (2H, m, 2 × ArH), 8.1 (1H, s, NH),
9.62 (1H, t, NH), 11.15 (1H, s, NH); found M+ 490.26866,
C27H34N6O3 requires M+ 490.26924. HPLC retention time )
12.86 min.
N-P h en yl-5-[2-(4,4-dim eth yl-2,5-dioxo-1-im idazolidin yl)-
et h yl]-3-[2-(d im et h yla m in o)et h yl]-1H-in d ole-2-ca r b ox-
a m id e (52). Method 10: white solid; MS m/z 462 (M + 1)+;
1H NMR δ 1.15 (6H, s, 2 × CH3), 2.2 (6H, s, 2 × NCH3), 2.61
(2H, m, CH2NMe2), 2.95 (2H, m, 5-CH2), 3.05 (2H, m, 3-CH2),
3.65 (2H, m, CH2Hyd), 7.08 (2H, m, H6, ArH), 7.35 (4H, m,
H7, H4, 2 × ArH), 7.66 (2H, d, 2 × ArH), 8.15 (1H, s, NH),
10.95 (1H, s, NH), 11.35 (1H, s, NH); found M+ 461.24100,
N-(3-Met h oxyb en zyl)-5-[2-(4,4-d im et h yl-2,5-d ioxo-1-
im id a zolid in yl)eth yl]-3-[2-(d im eth yla m in o)eth yl]-1H-in -
d ole-2-ca r boxa m id e (45). Method 5: purification by HPLC
gave the acetate salt of 45 as a cream powder; MS m/z 505
(M+); 1H NMR δ 1.13 (6H, s, 2 × CH3), 1.9 (4.5H, s, CH3CO2H),
2.08 (6H, s, 2 × NCH3), 2.48 (2H, m, CH2NMe2, under DMSO
peak), 2.92 (2H, m, 5-CH2), 3.05 (2H, m, 3-CH2), 3.61 (2H, m,
CH2Hyd), 3.75 (3H, s, OCH3), 4.5 (2H, d, CH2NHCO), 6.82 (1H,
d, H6), 6.9-7.1 (3H, m, H7, H4, ArH), 7.25 (3H, m, 3 × ArH),
8.1 (1H, s, NH), 9.65 (1H, t, NH), 11.15 (1H, s, NH); found M+
C
26H31N5O3 requires M+ 461.24269. Anal. (C26H31N5O3) C, H,
N. HPLC retention time ) 15.39 min.
N-(4-Flu or oben zyl)-3-(2-am in oeth yl)-5-[2-(4,4-dim eth yl-
2,5-d ioxo-1-im id a zolid in yl)eth yl]-1H-in d ole-2-ca r boxa m -
id e (53). Methods 6 and 9: The R-keto acid 25 (1.79 g, 10.0
mmol) and 1 drop of dry DMF were dissolved in dry dichlo-