ACS Chemical Neuroscience
Research Article
5.2.3i. 8-Ethyl-3-(methylthio)-5H-[1,2,4]triazino[5,6-b]indole
(39). The title compound (39) was synthesized from 29 (1.0 g,
4.34 mmol) and methyl iodide (0.27 mL, 4.34 mmol) according to
Method C. Light yellow solid (yield: 0.73 g, 69%); mp >250 °C; IR
(KBr, cm−1): 3062, 2961, 1599, 1480, 1318, 1204, 972, 806, 739; MS
(m/z): 245 [M + H]+.
5.2.3j. 3-(Methylthio)-8-(piperidin-1-yl)-5H-[1,2,4]triazino[5,6-b]-
indole (40). The title compound (40) was synthesized from 30 (1.0 g,
3.5 mmol) and methyl iodide (0.22 mL, 3.5 mmol) according to
Method C. Light yellow solid (yield: 0.71 g, 67%); mp >250 °C; IR
(KBr, cm−1): 3087, 2966, 1607, 1453, 1317, 1183, 1092, 976, 819,
778; MS (m/z): 300 [M + H]+.
5.2.4. Synthesis of Substituted 3-(Methylsulfonyl)-5H-[1,2,4]-
triazino[5,6-b]indole Derivatives (41−50). To a stirred solution of
substituted 3-(methylthio)-5H-[1,2,4]triazino[5,6-b]indoles (31−40,
1.0 g, 1 equiv) in anhydrous methylene chloride (20 mL) at 0−5 °C
was gradually added m-CPBA (2.25 equiv) in small portions over a
period of 5 min. The resultant reaction mixture was stirred at room
temperature maintaining anhydrous conditions for 24 h. Once the
reaction was completed (monitored by TLC), the reaction mixture
was washed repeatedly with a sodium bicarbonate solution (5%) and
with brine. The obtained organic phase was dried over anhydrous
magnesium sulfate, filtered, and concentrated under reduced pressure
to obtain a light greenish-yellow solid. The obtained products were
used as such in the next step without further purification.20
5.2.5. Synthesis of Substituted N-(Aminoalkyl)-5H-[1,2,4]-
triazino[5,6-b]indol-3-amine Derivatives (51−61). Method D: To
substituted 3-(methylsulfonyl)-5H-[1,2,4]triazino[5,6-b]indoles (41−
50, 0.5 g, 1 equiv) in tetrahydrofuran (15 mL) was added 6-
(pyrrolidin-1-yl)hexan-1-amine or methyl amine (5 equiv). The
reaction mixture was heated to reflux until the completion of the
reaction (monitored by TLC). Once the reaction was completed, the
reaction mixture was diluted with ice cold water (50 mL) and
extracted with ethyl acetate (30 mL × 3). The combined organic
phase was washed with a sodium bicarbonate solution (5%) and then
with brine, dried over anhydrous sodium sulfate, and concentrated
under reduced pressure. The crude material so obtained was further
purified by flash chromatography.20
(m, 2H, −NHCH2CH2, 4H, −CH2); MS (m/z): 417.31 [M]+, 419.09
[M + 2]+; RP-HPLC: purity = 99.1%, tR = 4.78 min.
5.2.5d. 6-Fluoro-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino-
[5,6-b] indol-3-amine (54). The title compound (54) was
synthesized from sulfone (44, 0.5 g, 1.88 mmol) and 6-(pyrrolidin-
1-yl)hexan-1-amine (3.20 g, 18.8 mmol) as per Method D. Yellow
solid (yield: 0.42 g, 61%); mp 221−220 °C; IR (KBr, cm−1): 3235,
1
3108, 2935, 1584, 1526, 1361, 1128, 1026; H NMR (DMSO-d6): δ
11.82 (bs, 1H, −NH), 7.82−7.87 (m, 1H, ArH), 7.34−7.41 (m, 1H,
ArH), 7.25−7.33 (m, 1H, ArH), 3.32−3.37 (m, 2H, −NHCH2),
2.30−2.38 (m, 6H, −NCH2), 1.55−1.67 (m, 6H, −NCH2CH2),
1.26−1.46 (m, 2H, −NHCH2CH2, 4H, −CH2); MS (m/z): 356
[M]+, 358 [M + 2]+; RP-HPLC: purity = 98.5%, tR = 3.62 min.
5.2.5e. 8-Fluoro-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino-
[5,6-b] indol-3-amine (55). The title compound (55) was
synthesized from sulfone (45, 0.5 g, 1.88 mmol) and 6-(pyrrolidin-
1-yl)hexan-1-amine (3.20 g, 18.8 mmol) as per Method D. Yellow
solid (yield: 0.42 g, 63%); mp 242−245 °C; IR (KBr, cm−1): 3233,
3106, 2935, 1528, 1360, 1293, 1128, 1025, 798, 735; 1H NMR
(DMSO-d6): δ 11.87 (bs, 1H, −NH), 7.83−7.86 (m, 1H, ArH),
7.36−7.39 (m, 1H, ArH), 7.26−7.31 (m, 1H, ArH), 3.34−3.36 (m,
2H, −NHCH2), 2.28−2.41 (m, 6H, −NCH2), 1.53−1.67 (m, 6H,
−NCH2CH2), 1.25−1.46 (m, 2H, −NHCH2CH2, 4H, −CH2); MS
(m/z): 356 [M]+, 358 [M + 2]+; RP-HPLC: purity = 98.4%, tR = 3.65
min.
5.2.5f. 8-Methyl-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino-
[5,6-b]indol-3-amine (56). The title compound (56) was synthesized
from sulfone (46, 0.5 g, 1.91 mmol) and 6-(pyrrolidin-1-yl)hexan-1-
amine (3.25 g, 19.1 mmol) as per Method D. Yellow solid (yield: 0.49
g, 73%); mp 178−181 °C; IR (KBr, cm−1): 3225, 3104, 2931, 1613,
1523, 1282, 1209, 1100, 801, 737; 1H NMR (DMSO-d6): δ 11.61 (bs,
1H, −NH), 7.80−7.91 (m, 1H, ArH), 7.15−7.36 (m, 2H, ArH),
3.29−3.40 (m, 2H, −NHCH2), 2.43 (s, 3H, ArCH3), 2.30−2.41 (m,
6H, −NCH2), 1.54−1.74 (m, 6H, −NCH2CH2), 1.10−1.49 (m, 2H,
−NHCH2CH2, 4H, −CH2); MS (m/z): 352.93 [M]+; RP-HPLC:
purity = 98.7%, tR = 3.81 min.
5.2.5g. 6,9-Dimethyl-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]-
triazino[5,6-b]indol-3-amine (57). The title compound (57) was
synthesized from sulfone (47, 0.5 g, 1.81 mmol) and 6-(pyrrolidin-1-
yl)hexan-1-amine (3.08 g, 18.1 mmol) as per Method D. Yellow solid
(yield: 0.46 g, 69%); mp 154−156 °C; IR (KBr, cm−1): 3228, 3010,
2930, 1599, 1518, 1264, 1121, 1032, 799, 751; 1H NMR (DMSO-d6):
δ 11.44 (bs, 1H, −NH), 7.14 (d, J = 7.5 Hz, 1H, ArH), 6.95 (d, J =
7.5 Hz, 1H, ArH), 3.32−3.34 (m, 2H, −NHCH2), 2.77 (s, 3H,
ArCH3), 2.41 (s, 3H, ArCH3), 2.29−2.38 (m, 6H, −NCH2), 1.56−
1.66 (m, 6H, −NCH2CH2), 1.26−1.46 (m, 2H, −NHCH2CH2, 4H,
5.2.5a. 8-Chloro-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino-
[5,6-b] indol-3-amine (51). The title compound (51) was
synthesized from sulfone (41, 0.5 g, 1.77 mmol) and 6-(pyrrolidin-
1-yl)hexan-1-amine (3.01 g, 17.7 mmol) as per Method D. Yellow
solid (yield: 0.46 g, 70%); mp >250 °C; IR (KBr, cm−1): 3421, 3075,
1
2930, 1618, 1547, 1365, 1142, 1107, 816; H NMR (DMSO-d6): δ
11.84 (bs, 1H, −NH), 8.02 (d, J = 2.2 Hz, 1H, ArH), 7.43 (dd, J =
8.5, 2.2 Hz, 1H, ArH), 7.36 (d, J = 8.5 Hz, 1H, ArH), 3.34−3.42 (m,
2H, −NHCH2), 2.42−2.54 (m, 6H, −NCH2), 1.59−1.71 (m, 4H,
−NCH2CH2), 1.52−1.57 (m, 2H, −NCH2CH2), 1.39−1.45 (m, 2H,
−NHCH2CH2), 1.25−1.34 (m, 4H, −CH2); MS (m/z): 373 [M]+,
375 [M + 2]+; RP-HPLC: purity = 96.7%, tR = 4.08 min.
−CH2); MS (m/z): 366.94 [M]+; RP-HPLC: purity = 97.5%, tR
4.05 min.
=
5.2.5h. 7,9-Dimethyl-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]-
triazino[5,6-b]indol-3-amine (58). The title compound (58) was
synthesized from sulfone (48, 0.5 g, 1.81 mmol) and 6-(pyrrolidin-1-
yl)hexan-1-amine (3.08 g, 18.1 mmol) as per Method D. Yellow solid
(yield: 0.41 g, 62%); mp 168−170 °C; IR (KBr, cm−1): 3372, 2931,
5.2.5b. 6,8-Dichloro-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]-
triazino[5,6-b]indol-3-amine (52). The title compound (52) was
synthesized from sulfone (42, 0.5 g, 1.58 mmol) and 6-(pyrrolidin-1-
yl)hexan-1-amine (2.69 g, 15.8 mmol) as per Method D. Yellow solid
(yield: 0.44 g, 68%); mp >250 °C; IR (KBr, cm−1): 3405, 3062, 2931,
1
1619, 1312, 1136, 841, 769; H NMR (DMSO-d6): δ 11.72 (bs, 1H,
1
−NH), 7.00 (s, 1H, ArH), 6.90 (s, 1H, ArH), 3.36−3.40 (m, 2H,
−NHCH2), 2.78 (s, 3H, ArCH3), 2.37−2.49 (m, 6H, −NCH2, 3H,
ArCH3), 1.55−1.71 (m, 6H, −NCH2), 1.42−1.49 (m, 2H,
−NHCH2CH2); 1.30−1.40 (m, 4H, −CH2); MS (m/z): 367 [M +
H]+; RP-HPLC: purity = 98.9%, tR = 4.06 min.
1608, 1528, 1376, 1312, 1076, 834, 724; H NMR (DMSO-d6): δ
7.43 (d, J = 2.1 Hz, 1H, ArH), 7.39 (d, J = 2.1 Hz, 1H, ArH), 3.35−
3.45 (m, 2H, −NHCH2), 2.36−2.51 (m, 6H, −NCH2), 1.56−1.71
(m, 6H, −NCH2CH2), 1.42−1.49 (m, 2H, −NHCH2CH2), 1.31−
1.40 (m, 4H, −CH2); MS (m/z): 407.31 [M]+, 409.25 [M + 2]+; RP-
HPLC: purity = 97.6%, tR = 6.88 min.
5.2.5i. 8-Ethyl-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino[5,6-
b] indol-3-amine (59). The title compound (59) was synthesized
from sulfone (49, 0.5 g, 1.81 mmol) and 6-(pyrrolidin-1-yl)hexan-1-
amine (3.08 g, 18.1 mmol) as per Method D. Yellow solid (yield: 0.49
g, 74%); mp 167−169 °C; IR (KBr, cm−1): 3226, 3012, 2933, 1613,
5.2.5c. 8-Bromo-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino-
[5,6-b] indol-3-amine (53). The title compound (53) was
synthesized from sulfone (43, 0.5 g, 1.53 mmol) and 6-(pyrrolidin-
1-yl)hexan-1-amine (2.61 g, 15.3 mmol) as per Method D. Yellow
solid (yield: 0.41 g, 64%); mp >250 °C; IR (KBr, cm−1): 3415, 3073,
1
1525, 1379, 1100, 877, 742; H NMR (DMSO-d6): δ 13.21 (bs, 1H,
1
−NH), 8.31 (d, J = 2.1 Hz, 1H, ArH), 7.71 (dd, J = 2.1 Hz, 8.4 Hz,
1H, ArH), 7.64 (d, J = 8.4 Hz, 1H, ArH), 3.36−3.37 (m, 2H,
−NHCH2), 2.82−2.87 (m, 2H, ArCH2CH3), 2.31−2.38 (m, 6H,
−NCH2), 1.54−1.66 (m, 6H, −NCH2CH2), 1.28−1.44 (m, 2H,
2929, 1615, 1524, 1453, 1142, 1106, 738; H NMR (DMSO-d6): δ
8.18 (d, J = 2.0 Hz, 1H, ArH), 7.58 (dd, J = 8.5, 2.0 Hz, 1H, ArH),
7.34 (d, J = 8.5 Hz, 1H, ArH), 3.35−3.40 (m, 2H, −NHCH2), 2.30−
2.38 (m, 6H, −NCH2), 1.55−1.66 (m, 6H, −NCH2CH2), 1.28−1.46
N
ACS Chem. Neurosci. XXXX, XXX, XXX−XXX