T. Ganesh et al. / Bioorg. Med. Chem. 16 (2008) 6903–6910
6909
J = 2.4 Hz, 1H), 6.30 (d, J = 2.8 Hz, 1H), 6.13 (t, J = 5.6 Hz, NH), 3.87 (s,
OCH3, 3H), 3.31 (dd, J = 7, 5.2 Hz, 2H), 2.46 (t, J = 6.8 Hz, 2H). 2.07 (d,
J = 2.4 Hz, 1H), 6.29 (d, J = 2.4 Hz, 1H), 6.13 (br, 1H), 3.89 (s, 3H),
2.48–2.58 (m, 6H), 1.77 (quintet, J = 8.0 Hz, 2H), 1.60–1.68 (m,
4H), 1.03 (t, J = 7.2 Hz, 6H). Compound 17c (5.3 mg, 27%). 1H
NMR (400 MHz, CDCl3): d 8.52 (dd, J = 1.6, 4.0 Hz, 1H), 7.91 (dd,
J = 1.6, 8.4 Hz, 1H), 7.28 (dd, J = 4.4, 8.4 Hz, 1H), 6.33 (d,
J = 2.8 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 6.07 (br, 1m), 3.88 (s, 3H),
3.26 (q, J = 6.8 Hz, 2H), 2.78 (septuplet, J = 6.4 Hz, 1H), 2.61 (t,
J = 6.8 Hz, 2H), 1.77 (quintet, J = 7.2 Hz, 2H), 1.46–1.59 (m, 4H),
1.03 (d, J = 6.0 Hz, 6H).
J = 7.2 Hz, 4H), 1.86(m, 2H), 1.70 (m, 2H), 0.88(d, J = 6.4 Hz, 12H). 13
C
NMR (100 MHz, CDCl3): d 159.7, 146.3, 144.5, 144.4, 135.6, 134.9,
129.9, 122.0, 96.7, 91.9, 64.2, 55.4, 53.2, 41.9, 27.2, 26.8, 21.2, 21.1.
HRMS calcd for C21H34N3O [M+H]: 344.26964; found: 344.26901
(
D
À1.83). Anal. Calcd for C21H33N3O: C, 73.43; H, 9.68; N, 12.01; ob-
served: C, 73.34; H, 9.88; N, 12.01.
4.4.5. 4-(6-Methoxyquinolin-8-ylamino)butanenitrile (15)
6-Methoxy-8-amino-quinoline (14) (1.5 mmol, 261.3 mg) and 4-
bromobutanenitrile (2.25 mmol, 333.0 mg) were refluxed in a mix-
ture of Et3N (2 ml) and MeOH (1 ml) for 24 h. More 4-bromobutane-
nitrile (2.25 mmol, 333.0 mg) was added and the mixture refluxed
for another 48 h. The mixture was concentrated to give a dark oily
residue which was purified by chromatography using hexane/EtOAc
(2:1) as eluent to afford compound 15a (148 mg, 40%). 1H NMR
(400 MHz, CDCl3): d 8.54 (dd, J = 1.6 Hz, 4.0 Hz, 1H), 7.95 (dd,
J=1.6 Hz, 8.4 Hz, 1H), 7.33 (dd, J = 8.0 Hz, 4.4 Hz, 1 H), 6.40 (d,
J = 2.8 Hz, 1H), 6.32 (d, J = 2.8 Hz, 1H), 6.20 (m, 1H), 3.90 (s, 3H),
3.49 (q, J = 6.4 Hz, 2H), 2.53 (t, J = 7.2 Hz, 2H), 2.11 (quintet,
J = 6.8 Hz, 2H).
4.6.2. 8-(5-(Diethylamino)pentylamino)quinolin-6-ol
dihydrobromide (10)
A solution of 17b (10 mg, 0.031 mmol) in HBr (1 ml, 48% aq)
was heated up to 120 °C in microwave initiator for 2.5 h. Cooled
down the reaction mixture, evaporated off the solvent by genevac
DD-4X evaporator. The resulting dark brown residue was purified
by silica gel chromatography to provide the title compound 10
(8 mg, 55%) as a pale brown solid. 1H NMR (400 MHz, DMSO-d6):
d 9.12 (br s, 1H), 8.60 (d, J = 3.9 Hz, 1H), 8.30 (d, J = 7.8 Hz, 1H),
7.56 (dd, J = 7.8, 4.6 Hz, 1H), 6.50 (s, 1H), 6.43 (s, 1H), 3.21 (t,
J = 7.0 Hz, 2H), 3.08 (quintet, J = 7.0 Hz, 4H), 3.03–2.98 (m, 2H),
1.74–1.62 (m, 4H), 1.47-1.39 (m, 2H), 1.16 (t, J = 7.0 Hz, 6H). 13C
NMR (100 MHz, DMSO-d6): d 158.5, 143.9, 142.0, 133.0, 132.9
130.7, 122.5, 100.4, 92.4, 54.5, 51.3, 46.8, 28.1, 24.4, 23.5, 9.2,
9.1. EI, m/z (C18H27N3O): calcd, 301.4; found: 302.3 (M+H). Anal.
Calcd for C18H29Br2N3OÁH2O: C, 44.92; H, 6.49; N, 8.73; observed:
C, 45.50; H, 6.26; N, 8.59.
4.5. Similar procedure was employed to make 15b
4.5.1. Compound 15b
Yield 41% . 1H NMR (400 MHz, CDCl3): d 8.54 (dd, J = 1.6 Hz,
4.4 Hz, 1H), 7.94 (dd, J = 1.6 Hz, 8.4 Hz, 1H), 7.32 (dd, J = 4.0 Hz,
8.4 Hz, 1H), 6.37 (d, J = 2.8 Hz, 1H), 6.29 (d, J = 2.8 Hz, 1H), 6.12
(m, 1H), 3.90 (s, 3H), 3.35 (q, J = 6.0 Hz, 2H), 2.42 (t, J = 7.2 Hz,
2H), 1.84-1.95 (m, 4H). Anal. Calcd for C15H17N3O: C, 70.56; H,
6.71; N, 16.46; Found: C, 70.63; H, 6.75; N, 16.48.
4.7. Similar procedure was employed to get 11 and 18a
4.7.1. 8-(5-(Isopropylamino)pentylamino)quinolin-6-ol (11)
(5.9 mg, 47%) 1H NMR (400 MHz, MeOH-d4): d 8.59–8.62 (m,
2H), 7.71 (dd, J = 5.2, 8.4 Hz, 1H), 6.70 (s, 1H), 3.22–3.29 (m, 3H),
2.94 (t, J = 8.0 Hz, 2H), 1.79 (quintet, J = 7.6 Hz, 2H), 1.68 (quintet,
J = 8.0 Hz, 2H), 1.53-1.59 (m, 2H), 1.22 (d, J = 6.8 Hz, 6H).
4.5.2. N1,N1-Diethyl-N4-(6-methoxyquinolin-8-yl)butane-1,4-
diamine (17b)
To a solution of compound 15a (1.0 mmol, 1 equiv, 255.31 mg)
in THF (5 ml) was added LAH (2.0 mmol, 2 equiv, 1.0 M in THF)
dropwise at À78 °C. Reaction mixture was kept at this temperature
for an additional 2 h, which was then allowed to slowly warm up to
room temperature. The reaction was quenched by addition of NaH-
CO3 (satd aq), extracted by EtOAc (3Â 5 ml), combined the organic
layer and washed with brine. Dried over Na2SO4 and evaporated off
the solvent to obtain crude compound 16b as an oily residue,
which was subjected to the next step without further purification.
To a solution of crude compound 16b in 5 ml of CH2Cl2 at 0 °C was
HRMS
288.20691(M+1).
calcd
for
C
17H25N3O:
287.19976;
observed:
4.7.2. 8-(4-(Diethylamino)butylamino)quinolin-6-ol (18a)
1H NMR (400 MHz, MeOH-d4): d 8.36 (dd, J = 1.6 Hz, 4.0 Hz, 1H),
7.83 (dd, J = 1.6 Hz, 8.4 Hz, 1H), 7.23 (dd, J = 4.4 Hz, 8.4 Hz, 1H),
6.27 (d, J = 2.0 Hz, 1H), 6.24 (d, J= 2.4 Hz, 1H), 3.08–3.16 (m, 6H),
1.76–1.83 (m, 4H), 1.20 (t, J = 7.6 Hz, 6H). MS, m/z (C17H25N3O):
calcd, 287.20; found: 288.40 (M+H).
added acetaldehyde (85 lL, 1.52 mmol). Reaction mixture was
Acknowledgments
kept at 0 °C for about 30 min, and then NaBH(OAc)3 (350 mg,
1.65 mmol) was added to the above mixture. The resulting solution
was allowed to warm to room temperature for another 3 h. The
mixture was diluted with CH2Cl2 (30 ml) and sequentially washed
with 10% NaHCO3 and brine. Drying over sodium sulfate followed
by filtration and concentration provided a residue that was puri-
fied by silica gel chromatography to obtain the product 17b
(90 mg, 43%). 1H NMR (400 MHz, MeOH-d4): d 8.61 (dd, J = 3.9,
1.6 Hz, 1H), 8.13 (dd, J = 8.6, 1.6 Hz, 1H), 7.36 (dd, J = 8.6, 3.9 Hz,
1H), 6.86 (d, J = 2.3 Hz, 1H), 6.83 (d, J = 2.3 Hz, 1H), 3.88 (s, 3H),
3.37 (quartet, J = 7.0 Hz, 2H), 2.47 (quartet, J = 7.0 Hz, 4H), 2.35 (t,
J = 7.8 Hz, 2H), 1.55–1.48 (m, 2H), 1.41-1.33 (m, 2H), 1.26-1.21
(m, 2H), 0.96 (t, J = 7.0 Hz, 6H). MS, m/z (C19H29N3O): calcd,
315.2; found, 316.4 (MH).
This work was financially supported by the US National Insti-
tutes of Health 1 U54 HG003918-02 and 1R03MH076499-01. We
also gratefully acknowledge National Cancer Institute (NCI) for
the generously supplying the samples listed in Figure 3.
References and notes
1. (a) Maloney, A.; Workman, P. Expert Opin. Biol. Ther. 2002, 2, 3–24; (b)
Whitesell, L.; Lindquist, S. L. Nat. Rev. Cancer 2005, 5, 761–772; (c) Jolly, C.;
Morimoto, R. I. J. Natl. Cancer Inst. 2000, 92, 1564; (d) Neckers, L.; Ivy, S. P. Curr.
Opin. Oncol. 2003, 15, 419–424; (e) Workman, P. Curr. Cancer Drug Targets 2003,
3, 297–330; (f) Chiosis, G.; Vilenchik, M.; Kim, J.; Solit, D. Drug Discov. Today
2004, 9, 881–888.
2. Kamal, A.; Thao, L.; Sensintaffar, J.; Zhang, L.; Boehm, M. F.; Fritz, L. C.; Burrows,
F. J. Nature 2003, 425, 407.
3. Workman, P. Trends Mol. Med. 2004, 10, 47–51.
4.6. Similar procedure was employed to get 17a and 17c
4. Neckers, L.; Schulte, T. W.; Mimnaugh, E. Invest. New Drugs 1999, 17, 361–373.
5. Ramanathan, R. K. et al Clin. Cancer Res. 2005, 11, 3385–3391.
6. (a) Agatsuma, T.; Ogawa, H.; Akasaka, K., et al Bioorg. Med. Chem. 2002, 10,
3445–3454; (b) Soga, S.; Shiotsu, Y.; Akinaga, S.; Sharma, S. V. Curr. Cancer Drug
Targets 2003, 3, 359–369; (c) Yang, Zhi-Qiang; Geng, X.; Solit, D.; Pratilas, C. A.;
Rosen, N.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 7881; (d) Moulin, E.;
4.6.1. Compound 17a
1H NMR (400 MHz, CDCl3): d 8.53 (dd, J = 1.6 Hz, 4.4 Hz, 1H),
7.92 (dd, J = 1.6, 8.4 Hz, 1H), 7.29 (dd, J = 4.0, 8.0 Hz, 1H), 6.34 (d,