PPTP as an Agonist of 5-HT3 Receptors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 10 2075
with EtOAc, and concentrated under reduced pressure. This
gave 1a : 4.54 g, 73% yield. The base of 1a could be converted
into the dihydrochloride salt as a white powder. Mp: 195 °C
(MeCN). 1H-NMR (DMSO-d6, 90 MHz): δ 3.33 (m, 4H, H
piperazine), 4.06 (m, 4H, H piperazine), 5.00 (m, 2H, NH2+),
6.76 (q, 1H, H7), 7.30 (q, 1H, H6), 7.46 (s, 2H, H2, H3), 8.00 (q,
1H, H8), 9.80 (s, 1H, NH+). IR: 3400 (m, NH+), 2700 (m, NH+),
1580 (s, CdN) cm-1. Anal. (C13H16Cl2N4S) C, H, Cl, N, S.
5-Su bstitu ted P yr r olo[1,2-a ]th ien o[3,2-e]pyr azin es 2a -
25a . 5-Chloropyrrolo[1,2-a]thieno[3,2-e]pyrazine (33) (2.08 g,
10 mmol) was added in DMF (10 mL) to the corresponding
piperazine (11 mmol) and Na2CO3 (1.27 g, 12 mmol). The
solution was heated under reflux for 2 h, cooled, and added to
100 mL of stirred water. The suspension was extracted three
times with 100 mL of Et2O. The organic layers were washed
three times with water, dried (MgSO4), decolorized with animal
charcoal, and filtered. The solvent was evaporated under
reduced pressure. The oil obtained was converted into its salt
(fumarate or hydrochloride). For the fumarate salts, the oil
was dissolved in acetone, 1 equiv of fumaric acid was added,
and the suspension was refluxed for 30 min; after cooling, the
precipitate was filtered and then dried first with anhydrous
ethyl ether and then at ambient temperature. For the
hydrochloride salts, the oil was dissolved in propan-2-ol with
a little heating if it was necessary for the dissolution, and an
excess of hydrochloric acid (3.5 equiv) was added; after 30 min
at 20 °C, the formed precipitate was filtered and dried with
anhydrous ethyl ether and then at ambient temperature. All
the salts were recrystallized from the appropriate solvent. This
gave series a (2a -25a ): 27-88% yield.
5-[4-(4-F lu or op h en yl)p ip er a zin o]p yr r olo[1,2-a ]th ien o-
[3,2-e]p yr a zin e h yd r och lor id e h yd r a te (7a ): obtained as
a white powder, 2.92 g, 72% yield. Mp: 238 °C (MeCN). 1H-
NMR (DMSO-d6, 200 MHz): δ 3.51 (m, 4H, H piperazine), 4.20
(m, 4H, H piperazine), 6.20 (m, 2H, NH+, H2O), 6.97 (m, 1H,
H7), 7.14 (m, 5H, H2′, H3′, H5′, H6′, H6), 7.51 (s, 2H, H2, H3),
8.11 (m, 1H, H8). IR: 3420 (m, NH+, H2O), 2660, 2560 (m,
NH+), 1595 (vs, CdN) cm-1
. Anal. (C19H20ClFN4OS) C, H,
Cl, N, S.
5-[4-[3-(Tr iflu or om et h yl)p h en yl]p ip er a zin o]p yr r olo-
[1,2-a ]th ien o[3,2-e]p yr a zin e d ih yd r och lor id e (8a ): ob-
tained as a white powder, 3.51 g, 80% yield. Mp: 208 °C
(MeCN). 1H-NMR (DMSO-d6, 200 MHz): δ 3.59 (m, 4H, H
piperazine), 3.80 (s, 2H, NH+), 4.10 (m, 4H, H piperazine), 6.97,
7.14 (m, 5H, H6, H7, H4′, H5′, H6′), 9.46 (m, 3H, H2, H3, H2′),
8.11 (m, 1H, H8). IR: 3400 (m, NH+), 2700, 2480 (m, NH+),
1580 (s, CdN) cm-1. Anal. (C20H19Cl2F3N4S) C, H, Cl, N, S.
5-Mor p h olin op yr r olo[1,2-a ]th ien o[3,2-e]p yr a zin e d i-
h yd r och lor id e (9a ): obtained as a white powder, 1.10 g, 33%
yield. Mp: 210 °C (MeCN).1H-NMR (DMSO-d6, 90 MHz): δ
3.89 (m, 8H, morpholine), 5.00 (s, 2H, NH+), 6.96 (q, 1H, H7),
7.48 (m, 3H, H2, H3, H6), 8.05 (m, 1H, H8). IR: 3420 (m, NH+),
2800 (m, NH+), 1690 (s, CdN) cm-1. Anal. (C13H15Cl2N3OS)
C, H, Cl, N, S.
5-P ip er id in op yr r olo[1,2-a ]t h ien o[3,2-e]p yr a zin e h y-
d r och lor id e (10a ): obtained as a yellow powder, 0.79 g, 27%
yield. Mp: 195 °C (MeCN). 1H-NMR (DMSO-d6, 90 MHz): δ
1.80 (s, 6H, piperidine), 3.99 (s, 4H, CH2-N-CH2 piperidine),
6.97 (q, 1H, H7, J 7,8 ) 2.70 Hz, J 7,6 ) 3.90 Hz), 7.50 (m, 3H,
H2, H3, H6), 8.08 (m, 1H, H8). IR: 3430 (m, NH+), 2720 (m,
NH+), 1595 (s, CdN) cm-1. Anal. (C14H16ClN3S) C, H, Cl, N,
S.
5-(4-Meth ylpiper azin o)pyr r olo[1,2-a ]th ien o[3,2-e]pyr a-
zin e m on ofu m a r a te (2a ): obtained as a white powder, 2.79
g, 72% yield. Mp: 200 °C (MeCN). 1H-NMR (DMSO-d6, 200
MHz): δ 2.42 (s, 3H, CH3), 2.65 (m, 4H, H piperazine), 3.65
(m, 4H, H piperazine), 6.66 (m, 2H, NH+, OH), 7.63 (s, 2H,
CHdCH), 6.82 (q, 1H, H7, J 7,8 ) 2.70 Hz, J 7,6 ) 3.90 Hz), 6.88
(q, 1H, H6, J 6,7 ) 3.90 Hz, J 6,8 ) 1.65 Hz), 7.20 (d, 1H, H3, J 3,2
) 5.70 Hz), 7.31 (d, 1H, H2, J 2,3 ) 5.70 Hz), 7.74 (q, 1H, H8,
J 8,7 ) 2.70 Hz, J 8,6 ) 1.65 Hz). IR: 3400 (m, OH), 3360 (m,
5-(1,2,5,6-Tet r a h yd r op yr id in o)p yr r olo[1,2-a ]t h ien o-
[3,2-e]p yr a zin e h yd r och lor id e (11a ): obtained as a white
powder, 2.45 g, 84% yield. Mp: 218 °C (MeCN). 1H-NMR
(DMSO-d6, 200 MHz): δ 2.34 (s, 2H, CH2), 3.71 (m, 2H, CH2),
4.08 (s, 2H, CH2), 5.00 (s, 1H, NH+), 5.82 (m, 2H, CHdCH),
6.82 (m, 2H, H6, H7), 7.20 (d, 1H, H3, J 3,2 ) 5.70 Hz), 7.34 (d,
1H, H2, J 2,3 ) 5.70 Hz), 7.71 (m, 1H, H8). IR: 3300 (m, NH+),
2780 (m, NH+), 1590 (s, CdN) cm-1. Anal. (C14H14ClN3S) C,
H, Cl, N, S.
NH+), 2660 (m, NH+), 1670 (s, CdO), 1600 (s, CdN) cm-1
.
Anal. (C18H20N4O4S) C, H, N, S.
5-(4-n -P r op ylp ip er a zin o)p yr r olo[1,2-a ]t h ien o[3,2-e]-
p yr a zin e h yd r och lor id e (3a ): obtained as a white powder,
1.51 g, 45% yield. Mp: >260 °C (MeCN). 1H-NMR (DMSO-
d6, 200 MHz): δ 0.94 (t, 3H, CH3, J ) 7 Hz), 1.71 (m, 2H, CH2),
3.11 (m, 2H, CH2), 3.25 (m, 4H, H piperazine), 3.71 (s, 1H,
NH+), 4.34 (m, 4H, H piperazine), 6.94 (m, 1H, H7), 7.22 (m,
1H, H6), 7.28 (d, 1H, H3, J 3,2 ) 5.70 Hz), 7.42 (d, 1H, H2), 7.91
(m, 1H, H8). IR: 3400 (s, NH+), 2660 (m, NH+), 1580 (vs, CdN)
cm-1. Anal. (C16H21ClN4S) C, H, Cl, N, S.
5-(4-Allylp ip er a zin o)p yr r olo[1,2-a ]t h ien o[3,2-e]p yr a -
zin e h yd r och lor id e (4a ): obtained as a white powder, 1.90
g, 57% yield. Mp: 254 °C (MeCN). 1H-NMR (DMSO-d6, 200
MHz): δ 3.39 (m, 4H, H piperazine), 3.77 (m, 4H, H pipera-
zine), 4.45 (d, 2H, CH2), 4.68 (s, 1H, NH+), 5.54 (m, 2H, CH2),
6.05 (m, 1H, CH), 6.97 (q, 1H, H7), 7.28 (q, 1H, H6), 7.42 (m,
2H, H2, H3), 8.02 (m, 1H, H8). IR: 3260 (m, NH+), 2540 (m,
NH+), 1600 (vs, CdN) cm-1. Anal. (C16H19ClN4S) C, H, Cl,
N, S.
5-(4-P h en ylpiper azin o)pyr r olo[1,2-a ]th ien o[3,2-e]pyr a-
zin e d ih yd r och lor id e (5a ): obtained as a white powder, 3.12
g, 79% yield. Mp: 250 °C (MeCN). 1H-NMR (DMSO-d6, 200
MHz): δ 3.65 (m, 4H, H piperazine), 4.34 (m, 4H, H pipera-
zine), 6.28 (m, 2H, NH+), 7.02 (m, 2H, H7, H6), 7.34, 7.54 (m,
7H, C6H5, H3, H2), 8.11 (m, 1H, H8). IR: 3420 (s, NH+), 2480,
2400 (m, NH+), 1570 (s, CdN) cm-1. Anal. (C19H20Cl2N4S) C,
H, Cl, N, S.
5-(4-P h en ylp ip er id in o)p yr r olo[1,2-a ]th ien o[3,2-e]p yr a -
zin e h yd r och lor id e (12a ): obtained as a white powder, 3.03
g, 82% yield. Mp: 250 °C (MeCN). 1H-NMR (DMSO-d6, 200
MHz): δ 1.94 (m, 4H, (CH2)2), 3.50 (m, 1H, CH), 3.57 (m, 2H,
CH2), 4.00 (m, 1H, NH+), 4.60 (m, 2H, CH2), 6.97 (m, 1H, H7),
7.25, 7.48 (m, 8H, C6H5, H2, H3, H6), 8.08 (m, 1H, H8). IR:
3400 (m, NH+), 2500 (m, NH+), 1590 (s, CdN) cm-1
. Anal.
(C20H20ClN3S) C, H, Cl, N, S.
5-(4-Ben zylp ip er a zin o)p yr r olo[1,2-a ]th ien o[3,2-e]p yr a -
zin e m on ofu m a r a te (13a ): obtained as a white powder, 3.39
g, 73% yield. Mp: 192 °C (MeCN). 1H-NMR (DMSO-d6, 90
MHz): δ 2.63 (m, 4H, H piperazine), 3.60 (m, 6H, CH2, H
piperazine), 6.63 (s, 2H, CHdCH), 6.83 (m, 2H, H6, H7), 7.30
(m, 7H, C6H5, H2, H3), 7.70 (m, 1H, H8), 10.65 (m, 2H, NH+,
OH). IR: 3420 (m, OH), 2500 (m, NH+), 1700 (s, CdO), 1570
(s, CdN) cm-1. Anal. (C24H24N4O4S) C, H, N, S.
5-[4-(4-F lu or oben zyl)p ip er a zin o]p yr r olo[1,2-a ]th ien o-
[3,2-e]p yr a zin e tr ih yd r och lor id e (14a ): obtained as a white
powder, 2.68 g, 61% yield. Mp: 180 °C (MeCN). 1H-NMR
(DMSO-d6, 90 MHz): δ 3.33 (m, 4H, H piperazine), 3.80 (m,
2H, CH2), 4.43 (m, 4H, H piperazine), 5.26 (m, 3H, NH+), 6.90
(q, 1H, H7), 7.23 (m, 3H, C6H2, H6), 7.40 (s, 2H, H2, H3), 7.73
(m, 2H, C6H2), 8.00 (m, 1H, H8). IR: 3400 (m, NH+), 2680,
2560 (m, NH+), 1590 (s, CdN) cm-1. Anal. (C20H22Cl3FN4S)
C, H, Cl, N, S.
5-[4-(2,4-Dich lor ob e n zyl)p ip e r a zin o]p yr r olo[1,2-a ]-
th ien o[3,2-e]p yr a zin e h yd r och lor id e (15a ): obtained as a
white powder, 2.67 g, 59% yield. Mp: 250 °C (MeCN). 1H-
NMR (DMSO-d6, 200 MHz): δ 3.42 (m, 4H, H piperazine), 4.85
(m, 2H, CH2), 4.51 (m, 4H, H piperazine), 5.71 (m, 1H, NH+),
6.91 (q, 1H, H7), 8.46 (q, 1H, H6), 7.42 (m, 2H, H2, H3), 7.54 (q,
1H, H5′, J 5′,3′ ) 1.90 Hz, J 5′,6′ ) 8.30 Hz), 7.71 (d, 1H, H3′, J 3′,5′
) 1.90 Hz), 8.00 (m, 1H, H8), 8.05 (d, 1H, H6′, J 6′,5′ ) 8.30 Hz).
IR: 3460 (m, NH+), 2700 (m, NH+), 1590 (s, CdN) cm-1. Anal.
(C20H19Cl3N4S) C, H, Cl, N, S.
5-[4-(4-Ch lor op h en yl)p ip er a zin o]p yr r olo[1,2-a ]th ien o-
[3,2-e]p yr a zin e h yd r och lor id e h yd r a te (6a ): obtained as
a white powder, 2.91 g, 69% yield. Mp: 170 °C (75% MeCN,
25% n-PrOH). 1H-NMR (DMSO-d6, 200 MHz): δ 2.51 (m, 4H,
H piperazine), 3.91 (m, 2H, NH+, H2O), 4.14 (m, 4H, H
piperazine), 6.97 (m, 4H, H3′, H5′, H7, H6), 7.25 (m, 2H, H2′,
H6′), 7.48 (d, 1H, H3), 7.57 (d, 1H, H2), 8.02 (m, 1H, H8). IR:
3400 (m, NH+), 2500, 2400 (m, NH+), 1595 (s, CdN) cm-1
.
Anal. (C19H20Cl2N4OS) C, H, Cl, N, S.