Synthesis and SAR of a New Model of Arylpiperazines
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 45
129.0, 138.8, 140.6, 151.0, 151.7 (Ar, Ph2C), 168.6 (C2), 173.5
(C5). Anal. (C30H31N3O2‚2HCl‚H2O) C, H, N.
1-[3-[4-(o-Meth oxyph en yl)piper azin -1-yl]pr opyl]-3-(9H-
flu or en -9-ylid en e)-2,5-p yr r olid in ed ion e (3g): yield 2.57 g
(41%); mp 212-215 °C (ethanol); IR (KBr, cm-1) 1760, 1700
(CON), 1620 (CdC); 1H NMR (DMSO-d6) δ 2.06-2,18 (m, 2H,
CH2), 3.12-3.20 (m, 6H, CH2-Npip, 2CH2-pip), 3.46-3.53 (m,
4H, 2CH2-pip), 3.66 (t, J ) 6.0 Hz, 2H, NCH2), 3.77 (s, 3H,
OCH3), 4.03 (s, 2H, CH2CO), 6.89-7.03 (m, 4H, phenyl), 7.34-
7.41 (m, 2H, H2′, H7′), 7.45-7.52 (m, 2H, H3′, H6′), 7.82 (d, J )
8.1 Hz, 1H, H8′), 7.85-7.90 (m, 2H, H4′, H5′), 9.36 (d, J ) 7.8
Hz, 1H, H1′); 13C NMR (DMSO-d6) δ 22.0 (CH2), 35.8 (NCH2),
37.5 (CH2CO), 47.0 (2CH2-pip), 51.1 (2CH2-pip), 53.3 (CH2-
Npip), 55.5 (OCH3), 112.1 (C6-phenyl), 118.5 (C3-phenyl), 123.8
(C5-phenyl), 125.7 (C3), 120.0, 120.4, 120.9, 127.4, 128.2, 128.3,
129.1, 130.6, 130.8, 135.5, 138.0, 139.2, 141.1, 141.2, 141.5
(fluorene, C1- and C4-phenyl), 151.9 (C2-phenyl), 169.8 (C2),
173.5 (C5). Anal. (C31H31N3O3‚2HCl‚H2O) C, H, N.
1-[3-[4-(m -Ch lor op h en yl)p ip er a zin -1-yl]p r op yl]-3-(9H-
flu or en -9-ylid en e)-2,5-p yr r olid in ed ion e (3h ): yield 1.82 g
(34%); mp 240-241 °C (ethanol); IR (KBr, cm-1) 1760, 1700
(CON), 1625 (CdC); 1H NMR (DMSO-d6) δ 2.07-2.18 (m, 2H,
CH2), 3.06-3.22 (m, 6H, CH2-Npip, 2CH2-pip), 3.49-3.53 (m,
2H, CH2-pip), 3.66 (t, J ) 6.3 Hz, 2H, NCH2), 3.84-3.89 (m,
2H, CH2-pip), 4.04 (s, 2H, CH2CO), 6.85 (d, J ) 8.1 Hz, 1H,
H6-phenyl), 6.95 (d, J ) 8.1 Hz, 1H, H4-phenyl), 7.03 (s, 1H,
H2-phenyl), 7.25 (t, J ) 8.1 Hz, 1H, H5-phenyl), 7.34-7.41 (m,
2H, H2′, H7′), 7.44-7.52 (m, 2H, H3′, H6′), 7.81-7.90 (m, 3H,
H4′, H5′, H8′), 9.35 (d, J ) 7.8 Hz, 1H, H1′); 13C NMR (DMSO-
d6) δ 22.3 (CH2), 35.7 (NCH2), 37.6 (CH2CO), 44.8 (2CH2-pip),
50.4 (2CH2-pip), 53.7 (CH2-Npip), 114.1 (C6-phenyl), 115.2 (C2-
phenyl), 125.6 (C3), 119.2, 119.9, 120.3, 127.3, 128.2, 129.0,
130.5, 130.7, 134.2, 135.3, 137.9, 141.1, 141.2, 141.4 (fluorene,
C3-, C4- and C5-phenyl), 150.8 (C1-phenyl), 169.7 (C2), 173.5
(C5). Anal. (C30H28ClN3O2‚HCl) C, H, N.
1-[3-[4-(o-Me t h oxyp h e n yl)p ip e r a zin -1-yl]p r op yl]-3-
(d ip h en ylm eth ylen e)-2,5-p yr r olid in ed ion e (3b): yield 1.17
g (20%); mp 129-130 °C (acetone); IR (KBr, cm-1) 1760, 1700
1
(CON), 1630 (CdC); H NMR (CDCl3) δ 1.91 (qt, J ) 7.2 Hz,
2H, CH2), 2.57 (t, J ) 6.9 Hz, 2H, CH2-Npip), 2.71-2.79 (m,
4H, 2CH2-pip), 3.20-3.28 (m, 4H, 2CH2-pip), 3.43 (s, 2H, CH2-
CO), 3.63 (t, J ) 6.9 Hz, 2H, NCH2), 3.85 (s, 3H, OCH3), 6.88-
7.03 (m, 4H, ArH), 7.17-7.39 (m, 10H, ArH); 13C NMR (CDCl3)
δ 24.1 (CH2), 35.8 (CH2CO), 36.7 (NCH2), 49.8 (2CH2-pip), 52.9
(2CH2-pip), 55.2 (OCH3), 55.7 (CH2-Npip), 121.3 (C3), 111.0,
118.1, 120.8, 123.0, 127.7, 128.3, 128.4, 128.6, 128.7, 128.9,
138.7, 140.5, 140.6, 151.6, 152.0 (Ar, Ph2C), 168.5 (C2), 173.4
(C5). Anal. (C31H33N3O3‚2HCl‚H2O) C, H, N.
1-[3-[4-(m -Ch lor op h e n yl)p ip e r a zin -1-yl]p r op yl]-3-
(d ip h en ylm eth ylen e)-2,5-p yr r olid in ed ion e (3c): yield 1.43
g (25%); mp 198-199 °C (acetone); IR (KBr, cm-1) 1760, 1700
1
(CON), 1630 (CdC); H NMR (CDCl3) δ 1.86 (qt, J ) 7.1 Hz,
2H, CH2), 2.48 (t, J ) 7.1 Hz, 2H, CH2-Npip), 2.60 (t, J ) 4.6
Hz, 4H, 2CH2-pip), 3.21 (t, J ) 4.9 Hz, 4H, 2CH2-pip), 3.41 (s,
2H, CH2CO), 3.63 (t, J ) 7.1 Hz, 2H, NCH2), 6.74-6.86 (m,
3H, H2-, H4- and H6-phenyl), 7.12-7.38 (m, 11H, ArH); 13C
NMR (CDCl3) δ 24.3 (CH2), 35.8 (CH2CO), 36.9 (NCH2), 48.3
(2CH2-pip), 52.6 (2CH2-pip), 55.7 (CH2-Npip), 121.4 (C3),
113.8, 115.7, 119.3, 127.7, 128.3, 128.4, 128.5, 128.7, 129.0,
129.9, 134.8, 138.8, 140.5, 151.7, 152.0 (Ar, Ph2C), 168.5 (C2),
173.5 (C5). Anal. (C30H30ClN3O2‚2HCl) C, H, N.
1-[3-[4-(m-(Tr iflu or om eth yl)p h en yl)piper a zin -1-yl]pr o-
p yl]-3-(d ip h en ylm et h ylen e)-2,5-p yr r olid in ed ion e (3d ):
yield 1.33 g (22%); mp 185-186 °C (acetone); IR (KBr, cm-1
)
1760, 1700 (CON), 1630 (CdC); 1H NMR (CDCl3) δ 1.85 (qt, J
) 6.9 Hz, 2H, CH2), 2.48 (t, J ) 6.9 Hz, 2H, CH2-Npip), 2.61
(t, J ) 4.8 Hz, 4H, 2CH2-pip), 3.24 (t, J ) 4.8 Hz, 4H, 2CH2-
pip), 3.41 (s, 2H, CH2CO), 3.63 (t, J ) 7.2 Hz, 2H, NCH2),
7.02-7.39 (m, 14H, ArH); 13C NMR (CDCl3) δ 24.2 (CH2), 35.7
(CH2CO), 36.7 (NCH2), 48.2 (2CH2-pip), 52.5 (2CH2-pip), 55.6
1-[3-[4-(m-(Tr iflu or om eth yl)ph en yl)p iper a zin -1-yl]p r o-
p yl]-3-(9H-flu or en -9-ylid en e)-2,5-p yr r olid in ed ion e (3i):
yield 1.87 g (31%); mp 215-218 °C (methanol); IR (KBr, cm-1
)
1
1760, 1700 (CON), 1625 (CdC); H NMR (DMSO-d6) δ 2.09-
2.19 (m, 2H, CH2), 3.09-3.29 (m, 6H, CH2-Npip, 2CH2-pip),
3.47-3.53 (m, 2H, CH2-pip), 3.66 (t, J ) 6.0 Hz, 2H, NCH2),
3.94-3.98 (m, 2H, CH2-pip), 4.01 (s, 2H, CH2CO), 7.15 (d, J )
7.8 Hz, 1H, H4-phenyl), 7.27-7.40 (m, 5H, H2-, H5- and H6-
phenyl, H2′, H7′), 7.44-7.51 (m, 2H, H3′, H6′), 7.81 (d, J ) 8.1
Hz, 1H, H8′), 7.85-7.90 (m, 2H, H4′, H5′), 9.35 (d, J ) 8.1 Hz,
1H, H1′); 13C NMR (DMSO-d6) δ 22.1 (CH2), 35.8 (NCH2), 37.5
(CH2CO), 44.9 (2CH2-pip), 50.5 (2CH2-pip), 53.2 (CH2-Npip),
3
(CH2-Npip), 111.8 (q, J C-F ) 4.0 Hz, C2-phenyl), 115.6 (q,
3J C-F ) 4.0 Hz, C4-phenyl), 118.5 (C6-phenyl), 121.3 (C3), 124.1
1
(q, J C-F ) 272.4 Hz, CF3), 127.6, 128.2, 128.3, 128.4, 128.6,
2
129.3, 129.9, 138.7, 140.4 (Ar, C5-phenyl), 131.1 (q, J C-F
)
31.8 Hz, C3-phenyl), 151.0, 151.5 (C1-phenyl, Ph2C), 168.4 (C2),
173.4 (C5). Anal. (C31H30F3N3O2‚2HCl) C, H, N.
1-[3-[4-(p-Flu or oph en yl)piper azin -1-yl]pr opyl]-3-(diph e-
n ylm eth ylen e)-2,5-pyr r olidin edion e (3e): yield 1.26 g (22%);
mp 217-218 °C (acetone); IR (KBr, cm-1) 1760, 1700 (CON),
1
111.8 (C2-phenyl), 115.9 (C4-phenyl), 124.4 (q, J C-F ) 273.0
2
1
Hz, CF3), 125.8 (C3), 130.2 (q, J C-F ) 31.7 Hz, C3-phenyl),
1630 (CdC); H NMR (DMSO-d6) δ 1.98 (qt, J ) 6.9 Hz, 2H,
119.4, 120.0, 120.4, 127.4, 128.2, 128.3, 129.2, 130.4, 130.7,
130.9, 135.5, 138.0, 141.2, 141.3, 141.6 (fluorene, C5- and C6-
phenyl), 150.0 (C1-phenyl), 169.8 (C2), 173.6 (C5). Anal.
(C31H28F3N3O2‚2HCl) C, H, N.
CH2), 3.04-3.28 (m, 6H, CH2-Npip, 2CH2-pip), 3.42-3.55 (m,
6H, 2CH2-pip, CH2CO), 3.65-3.75 (m, 2H, NCH2), 7.01-7.38
(m, 14H, ArH); 13C NMR (DMSO-d6) δ 24.2 (CH2), 35.2, 35.7
(CH2CO, NCH2), 46.0 (2CH2-pip), 50.6 (2CH2-pip), 53.0 (CH2-
2
1-[3-[4-(p-F lu or op h en yl)p ip er a zin -1-yl]p r op yl]-3-(9H-
flu or en -9-ylid en e)-2,5-p yr r olid in ed ion e (3j): yield 1.35 g
(26%); mp 295-298 °C (methanol); IR (KBr, cm-1) 1755, 1700
(CON), 1625 (CdC); 1H NMR (DMSO-d6) δ 2.09-2.18 (m, 2H,
CH2), 3.09-3.21 (m, 6H, CH2-Npip, 2CH2-pip), 3.49-3.55 (m,
2H, CH2-pip), 3.67 (t, J ) 6.1 Hz, 2H, NCH2), 3.69-3.73 (m,
2H, CH2-pip), 4.04 (s, 2H, CH2CO), 6.98-7.12 (m, 4H, phenyl),
7.33-7.41 (m, 2H, H2′, H7′), 7.45-7.52 (m, 2H, H3′, H6′), 7.82-
7.90 (m, 3H, H4′, H5′, H8′), 9.36 (d, J ) 8.1 Hz, 1H, H1′); 13C
NMR (DMSO-d6) δ 22.0 (CH2), 34.2 (NCH2), 36.8 (CH2CO), 46.1
Npip), 115.5 (d, J C-F ) 22.2 Hz, C3- and C5-phenyl), 117.9
(C2- and C6-phenyl), 122.8 (C3), 127.7, 127.9, 128.5, 128.7,
129.2, 139.5, 140.7 (Ar), 146.4 (C1-phenyl), 151.1 (Ph2C), 157.3
1
(d, J C-F ) 233.8 Hz, C4-phenyl), 168.4 (C2), 173.7 (C5). Anal.
(C30H30FN3O2‚2HCl‚H2O) C, H, N.
1-[3-(4-P h en ylp ip er a zin -1-yl)p r op yl]-3-(9H-flu or en -9-
ylid en e)-2,5-p yr r olid in ed ion e (3f): yield 0.78 g (14%); mp
260-262 °C (ethanol); IR (KBr, cm-1) 1750, 1700 (CON), 1630
1
(CdC); H NMR (DMSO-d6) δ 1.87 (qt, J ) 7.2 Hz, 2H, CH2),
2.58-2.70 (m, 6H, CH2-Npip, 2CH2-pip), 3.08-3.22 (m, 4H,
2CH2-pip), 3.67 (t, J ) 7.2 Hz, 2H, NCH2), 4.06 (s, 2H, CH2-
CO), 6.78 (t, J ) 7.2 Hz, 1H, H4-phenyl), 6.90 (d, J ) 7.2 Hz,
2H, H2- and H6-phenyl), 7.20 (t, J ) 7.2 Hz, 2H, H3- and H5-
phenyl), 7.35-7.40 (m, 2H, H2′, H7′), 7.45-7.52 (m, 2H, H3′,
H6′), 7.83 (d, J ) 7.8 Hz, 1H, H8′), 7.86-7.91 (m, 2H, H4′, H5′),
9.38 (d, J ) 7.8 Hz, 1H, H1′); 13C NMR (DMSO-d6) δ 24.4 (CH2),
36.5 (NCH2), 37.2 (CH2CO), 48.8 (2CH2-pip), 50.9 (2CH2-pip),
52.1 (CH2-Npip), 115.5 (C2- and C6-phenyl), 125.6 (C3), 128.8
(C3- and C5-phenyl), 119.0, 119.7, 120.2, 127.2, 128.0, 128.1,
128.9, 130.4, 130.6, 135.3, 137.8, 141.0, 141.2, 141.4 (fluorene,
C4-phenyl), 148.6 (C1-phenyl), 169.7 (C2), 173.3 (C5). Anal.
Calcd for C30H29N3O2‚2HCl‚H2O: C, 64.97; H, 6.00; N, 7.58.
Found: C, 65.44; H, 5.70; N, 7.39.
2
(2CH2-pip), 50.7 (2CH2-pip), 54.5 (CH2-Npip), 115.6 (d, J C-F
3
) 22.1 Hz, C3- and C5-phenyl), 117.8 (d, J C-F ) 7.8 Hz, C2-
and C6-phenyl), 125.8 (C3), 120.0, 120.4, 127.4, 128.2, 128.3,
128.8, 130.8, 132.1, 135.4, 138.0, 141.1, 141.2, 141.5 (fluorene),
146.5 (C1-phenyl), 156.5 (d, 1J C-F ) 237.5 Hz, C4-phenyl), 169.8
(C2), 173.6 (C5). Anal. (C30H28FN3O2‚HCl) C, H, N.
1-[4-(4-P h en ylp ip er a zin -1-yl)bu tyl]-3-(d ip h en ylm eth -
ylen e)-2,5-p yr r olid in ed ion e (4a ): yield 1.10 g (20%); mp
160-162 °C (acetone); IR (KBr, cm-1) 1775, 1710 (CON), 1640
1
(CdC); H NMR (CDCl3) δ 1.40-1.62 (m, 4H, -(CH2)2-), 2.32
(t, J ) 7.5 Hz, 2H, CH2-Npip), 2.50 (t, J ) 5.1 Hz, 4H, 2CH2-
pip), 3.11 (t, J ) 4.8 Hz, 4H, 2CH2-pip), 3.33 (s, 2H, CH2CO),
3.49 (t, J ) 7.2 Hz, 2H, NCH2), 6.76-6.84 (m, 3H, ArH), 7.09-