M. Maspero, et al.
BioorganicChemistry96(2020)103633
4.5.2. 3-(4-(Hexyloxy)-1,2,5-thiadiazol-3-yl)-1-(10-((1,2,3,4-
6.4 Hz, 4H; 2 × H6′, CH2eN), 2.51 (d, J = 3.7 Hz, 2H; H5′), 2.03–1.91
(m, 4H; 2 × H2, 2 × H3), 1.84 (dt, J = 13.2, 6.5 Hz, 4H; CH2eCH2eO,
HNeCH2eCH2), 1.65 (s, 2H; CH2eCH2eCH2eO), 1.50–1.30 (m, 14H;
tetrahydroacridin-9- yl)amino)decyl)pyridin-1-ium bromide (15b)
The title compound was prepared by reacting 13 (250 mg,
0.949 mmol) and 9b (396 mg, 0.949 mmol) in DMF (20 mL). After stan-
dard workup, 15b was obtained as a yellow oil (148 mg, 23%): Rf = 0.24
(DCM/MeOH 9:1). 1H NMR (400 MHz, CDCl3): δ 10.36 (d, J = 6.0 Hz, 1H;
H2′), 9.38 (s, 1H; H4′), 9.07 (dd, J = 9.7, 1.3 Hz, 1H; H6′), 8.25 (dd,
J = 8.2, 6.1 Hz, 1H; H5′), 7.94 (dd, J = 23.1, 8.3 Hz, 2H; H9, H6), 7.51
(ddd, J = 8.3, 6.8, 1.3 Hz, 1H; H7), 7.31 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H;
H8), 5.14 (t, J = 7.5 Hz, 2H; CH2eN+), 4.57 (t, J = 6.8 Hz, 2H; CH2eO),
3.55–3.42 (m, 2H; HNeCH2), 3.05 (s, 2H; H4), 2.70 (s, 2H; H1), 2.06 (dd,
J = 14.6, 7.5 Hz, 2H; CH2eCH2eO), 1.95–1.84 (m, 6H CH2eCH2eN+,
2 × H2, 2 × H3), 1.63 (dd, J = 14.0, 7.1 Hz, 2H; HNeCH2eCH2),
1.51–1.09 (m, 18H; HNe(CH2)2eCH2eCH2eCH2eCH2eCH2eCH2e
(CH2)2eN+, CH3eCH2eCH2eCH2e(CH2)2eO), 0.89 (t, J = 7.1 Hz, 3H;
CH3e(CH2)5eO) 13C NMR (101 MHz, CD3OD): δ 164.46, 157.91, 151.75,
145.57, 144.16, 143.84, 141.85, 139.82, 134.00, 133.23, 129.68, 126.41,
126.26, 120.22, 117.05, 112.81, 73.32, 63.63, 49.13, 32.64, 32.48, 31.55,
30.50, 30.41, 30.29, 30.13, 29.86, 29.28, 27.72, 27.20, 26.75, 24.88,
23.62, 22.98, 21.84, 14.39.
HNe(CH2)2eCH2eCH2eCH2eCH2eCH2eCH2eN,
CH3eCH2eCH2e
(CH2)3eO), 0.92 (t, J = 7.0 Hz, 3H; CH3e(CH2)5eO). 13C NMR
(101 MHz, CD3OD): δ 163.81, 155.88, 154.84, 147.84, 143.32, 132.15,
129.90, 129.85, 127.30, 125.57, 123.55, 118.89, 114.49, 72.19, 59.46,
54.06, 50.35, 49.39, 32.56, 31.82, 31.44, 30.76, 30.42, 30.19, 29.89,
28.50, 27.71, 27.51, 26.82, 25.44, 23.61, 23.48, 22.67, 14.35. MS (ESI)
m/z [M+H]+ calcd for C34H50BrN5OS+: 575.37, found: 576.25. HPLC
analysis: retention time = 8.275 min, purity 96.91%.
4.6.2. N-(10-(5-(4-(Hexyloxy)-1,2,5-thiadiazol-3-yl)-3,6-dihydropyridin-
1(2H)-yl)decyl)-1,2,3,4-tetrahydroacridin-9-amine (7-C10)
The title compound was prepared by reacting 15b (140 mg,
0.206 mmol), and NaBH4 (474 mg, 1.066 mmol) in 9 mL of MeOH.
After standard workup, 7-C10 was obtained as a brown oil (20 mg,
16%): Rf = 0.41 (DCM/MeOH 95:5). 1H NMR (400 MHz, CD3OD): δ
8.09 (d, J = 8.6 Hz, 1H; H9), 7.66 (d, J = 8.4 Hz, 1H; H6), 7.55 (t,
J = 7.6 Hz, 1H; H7), 7.33 (t, J = 7.7 Hz, 1H; H8), 6.99 (t, J = 3.8 Hz,
1H; H4′), 4.36 (t, J = 6.4 Hz, 2H; CH2eO), 3.57 (t, J = 7.1 Hz, 2H;
HNeCH2), 3.38 (s, 2H; H2′), 2.89 (s, 2H; H4), 2.63 (s, 2H; H1), 2.55 (t,
J = 5.7 Hz, 2H; H6′), 2.45–2.37 (m, 2H; CH2eN), 2.37–2.30 (m, 2H;
H5′), 1.87–1.80 (m, 4H; 2 × H2, 2 × H3), 1.73 (quint, J = 7.0 Hz, 2H;
HNeCH2eCH2), 1.60 (d, J = 7.2 Hz, 2H; CH2eCH2eO), 1.54–1.44 (m,
2H; CH2eCH2eCH2eO), 1.43–1.12 (m, 18H; HNe(CH2)2eCH2
eCH2eCH2eCH2eCH2eCH2eCH2eCH2eN, CH3eCH2eCH2e(CH2)3
eO), 0.82 (t, J = 7.0 Hz, 3H; CH3e(CH2)5eO). 13C NMR (101 MHz,
CD3OD): δ 163.86, 156.60, 154.94, 147.93, 139.81, 133.93, 131.23,
130.00, 129.88, 125.24, 125.14, 119.91, 115.45, 72.20, 59.55, 54.09,
50.39, 49.56, 32.57, 32.01, 30.79, 30.75, 30.52, 30.45, 30.44, 30.25,
29.91, 28.63, 27.78, 27.58, 26.83, 25.72, 23.75, 23.61, 23.10, 14.32.
MS (ESI) m/z [M+H]+ calcd for C36H54BrN5OS+: 603.40, found:
604.25. HPLC analysis: retention time = 8.3 min, purity 96.7%.
4.5.3. 3-(4-(Hexyloxy)-1,2,5-thiadiazol-3-yl)-1-(12-((1,2,3,4-
tetrahydroacridin-9- yl)amino)dodecyl)pyridin-1-ium bromide (15c)
The title compound was prepared by reacting 13 (100 mg,
0.380 mmol) and 9c (200 mg, 0.449 mmol) in DMF (10 mL). After stan-
dard workup, 15c was obtained as a yellow oil (60 mg, 22%): Rf = 0.26
(DCM/MeOH 9:1). 1H NMR (400 MHz, CD3OD): δ 9.61 (s, 1H; H2′), 9.24
(dt, J = 8.3, 1.3, 1.2 Hz, 1H; H4′), 9.07 (d, J = 6.1 Hz, 1H; H6′), 8.39 (d,
J = 8.3 Hz, 1H; H5′), 8.25 (dd, J = 8.1, 6.2 Hz, 1H; H9), 7.85 (ddd,
J = 8.1, 6.9, 1.1 Hz, 1H; H6), 7.77 (dd, J = 8.5, 0.9 Hz, 1H; H7), 7.58
(ddd, J = 8.4, 6.9, 1.3 Hz, 1H; H8), 4.75 (t, J = 7.6 Hz, 2H; CH2eN+),
4.63 (t, J = 6.7 Hz, 2H; CH2eO), 3.95 (t, J = 7.4 Hz, 2H; HNeCH2), 3.02
(t, J = 5.6 Hz, 2H; H4), 2.71 (t, J = 5.4 Hz, 2H; H1), 2.09 (quint,
J = 7.9 Hz, 2H; CH2eCH2eO), 2.01–1.92 (m, 6H; CH2eCH2eN+
,
2 × H2, 2 × H3), 1.83 (quint, J = 7.7 Hz, 2H; HNeCH2eCH2), 1.57–1.25
(m, 22H; HNe(CH2)2eCH2eCH2eCH2eCH2eCH2eCH2eCH2eCH2e
(CH2)2eN+, CH3eCH2eCH2eCH2e(CH2)2eO), 0.93 (t, J = 7.1 Hz, 3H;
CH3e(CH2)5eO). 13C NMR (101 MHz, CD3OD): δ 178.08, 164.50, 158.04,
151.69, 145.55, 144.15, 143.90, 141.86, 139.80, 134.12, 133.30, 129.67,
126.52, 126.31, 120.11, 117.07, 112.86, 73.35, 63.67, 49.07, 32.68,
32.50, 31.56, 30.64, 30.54, 30.35, 30.19, 29.90, 29.31, 27.75, 27.24,
26.79, 24.89, 23.65, 22.99, 22.95, 21.86, 14.38.
4.6.3. N-(12-(5-(4-(Hexyloxy)-1,2,5-thiadiazol-3-yl)-3,6-dihydropyridin-
1(2H)-yl)dodecyl)-1,2,3,4-tetrahydroacridin-9-amine (7-C12)
The title compound was prepared by reacting 15c (200 mg,
0.282 mmol), and NaBH4 (86 mg, 2.26 mmol) in 12 mL of MeOH. After
standard workup, 7-C12 was obtained as a brown oil (84 mg, 47%):
Rf = 0.46 (DCM/MeOH 95:5). 1H NMR (400 MHz, CD3OD): δ 8.35 (d,
J = 8.7 Hz, 1H; H9), 7.86–7.73 (m, 2H; H6, H7), 7.55 (ddd, J = 8.5,
6.6, 1.6 Hz, 1H; H8), 7.11 (dd, J = 3.7, 2.0 Hz, 1H; H4′), 4.46 (t,
J = 6.5 Hz, 2H; CH2eO), 3.90 (t, J = 7.2 Hz, 2H; HNeCH2), 3.66–3.53
(m, 2H; H2′), 3.01 (s, 2H; H4), 2.78–2.65 (m, 4H; 2 × H1, 2 × H6′),
2.65–2.55 (m, 2H; CH2eN), 2.48 (s, 2H; H5′), 1.96 (s, 4H;
4.6. General procedure for the synthesis of target compounds 7-Cn
To a solution of intermediate pyridinium salt (15) (1 equiv) in
MeOH (0.03 M), a solution of NaBH4 (5–8 equiv) in MeOH (0.5 M) was
added dropwise at 0 °C, and the reaction was stirred for 5 h at room
temperature. After quenching with a saturated solution of NaHCO3, the
aqueous phase was extracted with DCM. The pooled organic phases
were dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude reaction mixtures were submitted to silica gel
column chromatography (eluent: DCM/MeOH 95:5), providing the pure
target derivatives 7-C8, 7-C10 and 7-C12.
H2), 1.90–1.71 (m, 4H;
2 × H3, HNeCH2eCH2), 1.69–156
(m, 2H; CH2eCH2eO), 1.56–1.14 (m, 24H; HNe(CH2)2e
CH2eCH2eCH2eCH2eCH2eCH2eCH2eCH2eCH2eCH2eN, CH3eCH2
eCH2eCH2e(CH2)2eO), 0.92 (t, J = 7.0 Hz, 3H; CH3e(CH2)5eO). 13
C
NMR (101 MHz, CD3OD): δ 163.84, 157.47, 152.49, 147.66, 133.59,
129.75, 129.50, 127.33, 126.27, 126.11, 121.02, 117.55, 113.28,
72.24, 59.38, 53.83, 50.28, 49.24, 32.57, 31.59, 30.63, 30.60, 30.56,
30.53, 30.25, 29.90, 29.88, 28.57, 27.70, 27.36, 27.24, 26.82, 26.51,
25.01, 23.61, 23.13, 22.08, 14.34. MS (ESI) m/z [M+H]+ calcd for
4.6.1. N-(8-(5-(4-(Hexyloxy)-1,2,5-thiadiazol-3-yl)-3,6-dihydropyridin-
1(2H)-yl)octyl)-1,2,3,4-tetrahydroacridin-9-amine (7-C8)
C
38H58BrN5OS+: 631.43, found: 632.35. HPLC analysis: retention
time = 8.9 min, purity 95.7%.
The title compound was prepared by reacting 15a (100 mg,
0.153 mmol), and NaBH4 (35 mg, 0.919 mmol) in 7 mL of MeOH. After
standard workup, 7-C8 was obtained as a brown oil (21 mg, 24%):
Rf = 0.31 (DCM/MeOH 95:5). 1H NMR (400 MHz, CD3OD): δ 8.38 (d,
J = 8.7 Hz, 1H; H9), 7.81 (dt, J = 18.7, 7.9 Hz, 2H; H6, H7), 7.57 (dd,
J = 11.2, 4.3 Hz, 1H; H8), 7.14 (s, 1H; H4′), 4.47 (t, J = 6.5 Hz, 2H;
CH2eO), 3.94 (t, J = 7.3 Hz, 2H; HNeCH2), 3.65 (s, 2H; H2′), 3.02 (d,
J = 5.7 Hz, 2H; H4), 2.83 (t, J = 5.8 Hz, 2H; H1), 2.68 (dd, J = 9.6,
4.7. General procedure for the synthesis of target compounds 8-Cn
The reaction was conducted under Argon atmosphere. To a solution
of Xanomeline 3 (1 equiv) in dry CH3CN (0.1 M) a solution of func-
tionalized tacrine bromide (9) (1 equiv) in dry CH3CN (0.1 M) was
added. The mixture was reacted for 10 h at 80 °C in a microwave ap-
paratus (pressure: 19 atm, power of 500 W). The crude reaction
10