26
M. Blaess et al. / European Journal of Medicinal Chemistry xxx (2017) 1e32
(t, 1H, J ¼ 7.45 Hz, CH), 6.65e6.70 (m, 2H, CH-Ar), 6.73e6.76 (m, 1H,
CH-Ar), 7.01e7.04 (m, 1H, CH-Ar), 7.12e7.16 (m, 4H, CH-Ar),
7.18e7.20 (m, 2H, CH-Ar), 7.26e7.28 (m, 1H, CH-Ar). 13C NMR
4.4.43. NB 18 9-[[4-[2-(4-methoxyphenyl)ethyl]piperazin-1-yl]
methyl]carbazole (99)
Modified method A, reactant: 19. 19 (0.15 g, 0.90 mmol) was
dissolved in toluene (30 mL), treated with n-BuLi (0.67 mL,
1.08 mmol), 98 (0.28 g, 0.99 mmol) and TIBA (0.36 g, 0.99 mmol)
and the mixture refluxed overnight. Purification by column chro-
matography (chloroform-methanol, 99:1 (v/v)) afforded a yellow
(90.6 MHz, CDCl3):
d 26.62 (CHCH2CH2), 32.68 (2CH2-Ar), 33.77
(CH2Ph), 42.71 (CH3), 55.87, 55.92 (2OCH3), 55.69 (CH2NMe), 58.99
(CH2NMe), 111.30, 112.02, 120.57 (3CH-Ar), 126.05, 127.54, 128.57,
130.03 (4CH-Ar), 128.30 (C¼CH), 132.21 (C-Ar), 137.03, 139.45
(CCHC), 139.92, 141.04 (2C(CH2)2C), 144.28 (C-Ar), 147.49, 148.93
~
syrup: 99 (0.086 g, 23%). 1H NMR (250 MHz, CDCl3):
d 2.27 (t, 2H,
(2COMe). IR (Film):
n
(cmꢀ1) 2935 (s), 2835 (s), 2790 (m), 1628 (m,
CH2Ph), 2.55e2.61 (m, 8H, 4CH2-piperazine), 2.72e2.83 (m, 4H,
2CH2N), 3.79 (s, 3H, OCH3), 4.42e4.49 (t, 2H, J ¼ 6.89 Hz, -NCH2),
6.81e6.86 (m, 2H, CH-Ar), 7.10e7.22 (m, 4H, CH-Ar), 7.39e7.50 (m,
4H, CH-Ar), 8.08e8.13 (m, 2H, CH-Ar). 13C NMR (62.9 MHz, CDCl3):
C¼C),1592 (m),1516 (m),1464 (s),1418 (m),1360 (m),1263 (s),1237
(s), 1156 (m), 881 (s), 739 (s). MS (EI, 145 ꢁC): m/z (%) 427 (3) [Mþ],
276 (22) [Mþ- CH2Ph(OMe)2], 209 (12), 208 (100) [Mþ-
C3H4NC2H4Ph(OMe)2], 193 (9) [Mþ- C4H7NC2H4Ph(OMe)2], 178 (9)
[naphthoyl]. HRMS C29H33NO2: found 427.2510 [calcd. 427.2511].
d
32.58 (CH2Ph), 41.72 (-NCH2), 49.96 (CH2N-), 51.44 (CH2-pipera-
zine), 52.98 (CH2-piperazine), 55.43 (OCH3), 57.45 (CH2N-), 108.30,
119.01, 119.89, 125.31 (4CH-Ar), 114.23, 129.10 (2CH-Ar), 122.12 ꢀ(C1-
~
C), 130.86 (C-Ar), 139.23 (C-N), 158.33 (COMe). IR (Film):
n
(cm
)
2852 (s, OMe), 2312 (m), 1733 (m), 1647 (m), 1512 (s), 1453 (s), 1326
(m), 1247 (s), 1154 (m), 1037 (m), 848 (w), 738 (s). MS (EI, 154 ꢁC):
m/z (%) 413 (7) [Mþ], 239 (21), 292 (100) [Mþ- PhOMe], 234 (15),
180 (14) [Mþ- CH2NC4H8NC2H4PhOMe], 167 (22) [carbazole]. HRMS
4.4.41. NB 31 3-(5,6-dihydrodibenzo[2,1-b:10,20-e][7]annulen-11-
ylidene)-N-[2-(4-methoxyphenyl)ethyl]-N-methyl-propan-1-amine
(91)
Method C, reactant: 89. 89 (0.80 g, 3.04 mmol) was dissolved in
THF (50 mL), n-BuLi (7.28 mL, 3.65 mmol), 7 (0.62 g, 3.65 mmol) in
10 mL toluene and TIBA (1.35 g, 3.65 mmol) were added. The
mixture was refluxed 48 h and the product was purified to yield an
orange syrup: 91 (NB 31) (0.38 g, 31%). 1H NMR (360 MHz, CDCl3):
C27H31N3O: found 413.2466 [calcd. 413.2467].
4.4.44. NB 42 9-[3-[(3S,5R)-4-[2-(3,4-dimethoxyphenyl)ethyl]-3,5-
dimethyl-piperazin-1-yl]propyl]carbazole (104)
Method C, reactant: 103. 103 (0.50 g, 1.56 mmol) was dissolved
in toluene (40 mL), n-BuLi (1.16 mL, 1.86 mmol), 4 (0.37 g,
1.86 mmol) and TIBA (0.69 g, 1.86 mmol) were added and the
mixture refluxed for 48 h. After processing and purification a light
yellow volatile oil was obtained: 104 (NB 42) (0.208 g, 28%). 1H
d
2.22 (s, 3H, CH3), 2.27e2.31 (tt, 2H, J ¼ 7.72 Hz, CHCH2CH2),
2.29e2.33 (dt, 2H, J ¼ 7.72 Hz, CH2NMe), 2.49e2.52 (m, 2H, CH2-Ar),
2.53e2.55 (m, 2H, CH2-Ar), 2.62e2.67 (m, 4H, CH2CH2Ph), 3.76 (s,
3H, OCH3), 5.84e5.88 (t, 1H, J ¼ 7.35 Hz, CH), 6.77e6.79 (m, 2H, CH-
Ar), 7.01e7.05 (m, 2H, CH-Ar), 7.11e7.15 (m, 4H, CH-Ar), 7.17e7.20
(m, 2H, CH-Ar), 7.25e7.29 (m, 2H, CH-Ar). 13C NMR (62.9 MHz,
NMR (360 MHz, CDCl3):
d 1.12 (s, 3H, CH3), 1.14 (s, 3H, CH3),
1.77e1.83 (t, 2H, J ¼ 10.69 Hz, CH2-piperazine), 1.99e2.07 (tt, 2H,
J ¼ 6.84 Hz, CH2CH2CH2), 2.24e2.28 (t, 2H, J ¼ 6.84 Hz, CH2N),
2.62e2.70 (m, 4H, CH2-piperazine, CH2Ph), 2.78e2.82 (m, 2H,
2CHMe), 2.96e3.02 (m, 2H, CH2N), 3.84 (s, 3H, OCH3), 3.87 (s, 3H,
OCH3), 4.36e4.40 (t, 2H, J ¼ 6.73 Hz, -NCH2), 6.66e6.70 (m, 2H, CH-
Ar), 6.78e6.80 (m, 1H, CH-Ar), 7.19e7.25 (m, 4H, CH-Ar), 7.42e7.48
CDCl3):
d 27.22 (CHCH2CH2), 32.61 (2CH2-Ar), 33.75 (CH2Ph), 42.03
(CH3), 55.21 (OCH3), 56.98 (CH2NMe), 59.35 (CH2NMe), 113.73,
129.54 (2CH-Ar), 125.71, 126.95, 127.98, 129.45 (4CH-Ar), 128.62
(C¼C), 132.51 (C-Ar), 137.03, 139.32 (2CCHC), 140.08, 141.30
(cmꢀ1) 2932
~
(2C(CH2)2C), 143.47 (C-Ar), 157.83 (COMe). IR (Film): n
(s, CH3), 2834 (s, OMe), 1612 (m, C¼C), 1512 (s), 1486 (s), 1454 (m),
1301 (m), 1247 (s), 1177 (m), 825 (m), 755 (s). MS (EI, 125 ꢁC): m/z
(%) 397 (14) [Mþ], 267 (28) [Mþ- CH2PhOMe], 193 (19) [Mþ-
C4H7NC2H4PhOMe], 178 (80) [naphthoyl]. HRMS C28H31NO: found
397.2407 [calcd. 397.2406].
(m, 4H, CH-Ar). 13C NMR (90.6 MHz, CDCl3):
d 18.03 (2CH3), 25.86
(CH2CH2CH2), 29.02 (CH2Ph), 40.59 (-NCH2), 50.04 (CH2N-), 53.42
(2CHMe), 54.83 (CH2N-), 55.85, 55.91 (2OCH3), 61.13 (-N(CH2)2),
108.83, 118.76, 120.26, 125.50 (4CH-Ar), 111.45, 111.94, 120.49 (3CH-
Ar), 122.83 (C-C), 136.02 (C-Ar), 140.49 (C-N), 147.38, 148.95
~
(2COMe). IR (Film): n
(cmꢀ1) 2935 (s, CH3), 2819 (s, OMe), 2810 (s,
OMe), 2316 (m), 1627 (m), 1598 (m), 1510 (s), 1449 (s), 1373 (m),
1249 (s), 1202 (s), 1149 (m), 1039 (m), 752 (s), 724 (s); MS (EI,
153 ꢁC): m/z (%) 485 (6) [Mþ], 335 (26), 334 (93) [Mþ-
4.4.42. NB 21 3-(11,12-dihydro-6H-benzo[c][1]benzazocin-5-yl)-N-
[2-(4-methoxyphenyl)ethyl]-N-methyl-propan-1-amine (95)
Method C, reactant: 94. 94 (0.20 g, 0.71 mmol) was dissolved in
THF (30 mL), n-BuLi (0.49 mL, 0.79 mmol), 7 (0.15 g, 0.86 mmol) and
TBAI (0.32 g, 0.86 mmol) were added. The mixture was refluxed
overnight; after purification a yellow syrup was obtained: 95 (NB
CH2Ph(OMe)2],
C2H4NC6H12NC2H4Ph(OMe)2], 167 (4) [carbazole]. HRMS
31H39N3O2: found 485.3049 [calcd. 485.3042]. Anal (C31H39N3O2):
181
(14),
180
(100)
[Mþ-
C
C, H, N.
21) (0.084 g, 28%). 1H NMR (360 MHz, CDCl3):
d 1.60e1.70 (m, 2H,
CH2CH2CH2), 2.17 (s, 3H, CH3), 2.33e2.37 (m, 2H, CH2NMe),
2.43e2.47, 2.59e2.64 (2m, 4H, 2CH2-Ar), 3.06e3.10 (m, 2H, -NCH2),
3.21e3.26 (m, 4H, CH2CH2Ph), 3.77 (s, 3H, OCH3), 4.16 (s, 2H, CH2-
Ar), 6.79e6.85 (m, 3H, CH-Ar), 6.99e7.13 (m, 6H, CH-Ar). 13C NMR
4.4.45. NB 19 9-[3-[(3S,5R)-4-[2-(4-methoxyphenyl)ethyl]-3,5-
dimethyl-piperazin-1-yl]propyl]carbazole (105)
Method C, reactant: 103. 103 (0.90 mg, 2.80 mmol) was dis-
solved in toluene (50 mL), deprotonated with n-BuLi (2.10 mL,
3.36 mmol), treated with 7 (0.57 g, 3.36 mmol) and TIBA (1.24 g,
3.36 mmol). The mixture was refluxed for 48 h, processing and
purification gave a light yellow volatile oil: 105 (NB 19) (0.42 g,
(62.9 MHz, CDCl3):
d 25.60 (CH2CH2CH2), 32.59, 33.43 (2CH2-Ar),
34.38 (CH2Ph), 41.98 (CH3), 51.55 (-NCH2), 55.26 (OCH3), 55.32
(CH2-Ar), 59.65 (CH2NMe), 60.89 (CH2NMe), 113.81, 121.90, 125.96,
126.74, 127.17, 128.90, 129.73, 131.12 (8CH-Ar), 119.68, 130.92 (2CH-
Ar), 132.34 (C-Ar), 136.32, 137.78 (2C(CH2)2C), 141.91 (C-N), 150.36
~
33%). 1H NMR (250 MHz, CDCl3):
d 1.11 (s, 3H, CH3), 1.14 (s, 3H, CH3),
1.75e1.84 (t, 2H, J ¼ 10.68 Hz, CH2-piperazine), 1.98e2.09 (tt, 2H,
J ¼ 6.78 Hz, CH2CH2CH2) 2.24e2.29 (t, 2H, J ¼ 6.78 Hz, CH2N),
2.62e2.70 (m, 4H, CH2-piperazine, CH2Ph), 2.77e2.85 (m, 2H,
2CHMe), 2.94e3.01 (m, 2H, CH2N), 3.78 (s, 3H, OCH3), 4.37e4.42 (t,
2H, J ¼ 6.78 Hz, -NCH2), 6.83e6.87 (m, 2H, CH-Ar), 7.06e7.10 (m,
2H, CH-Ar), 7.19e7.25 (m, 4H, CH-Ar), 7.44e7.48 (m, 2H, CH-Ar),
(CCH2N), 157.92 (COMe). IR (Film): n
(cmꢀ1) 2857 (s, CH3), 2797 (s,
CH3), 2344 (m), 1612 (m), 1513 (s), 1494 (s), 1353 (m), 1247 (s), 1178
(m), 1037 (s), 825 (m), 759 (s). MS (EI, 130 ꢁC): m/z (%) 414 (2) [Mþ],
293 (14) [Mþ- CH2PhOMe], 222 (43) [Mþ- C3H7 NC2H4PhOMe], 209
(14), 208 (20) [tetrahydrodibenz[b,f]azocine]. HRMS C28H34N2O:
found 414.2675 [calcd. 414.2671]. Anal (C28H34N2O): C, H, N.
8.08e8.11 (m, 2H, CH-Ar). 13C NMR (62.9 MHz, CDCl3):
d 17.99
Please cite this article in press as: M. Blaess, et al., NB 06: From a simple lysosomotropic aSMase inhibitor to tools for elucidating the role of
j.ejmech.2017.09.021