High Affinity Serotonin and Dopamine Receptor Ligands
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5 769
ethyl acetate as the solvent to give the bromide 33 as an off
white solid (3.56 g, 67% yield). Mp 96-7 °C; 1H NMR (400
MHz, CDCl3) δ 8.20 (d, J ) 5 Hz, 2 H), 6.44 (t, J ) 5 Hz, 1 H),
4.99 (d, J ) 8 Hz, 1 H), 3.72 (m, 1 H), 3.42 (t, J ) 7 Hz, 2 H),
2.09 (d, J ) 10 Hz, 2 H), 1.79 (d, J ) 14 Hz, 2 H), 1.75 (q, J )
7 Hz, 2 H), 1.45 (m, 1 H), 1.17 (dd, J ) 10, 24 Hz, 2 H), 1.08
(dd, J ) 10, 24 Hz, 2 H); CIMS 284 (M + H, base). Anal.
(C12H18BrN3) C, H, N, Br.
tr a n s-P yr im id in -2-yl-(4-{2-[4-[3-(tr iflu or om eth yl)p h e-
n yl]p ip er a zin -1-yl]eth yl}cycloh exyl)a m in e (41). A mix-
ture of trans-[4-(2-Bromoethyl)cyclohexyl]pyrimidin-2-ylamine
33 (Het is 2-pyrimidinyl) (0.26 g, 0.91 mmol), 1-[3-(trifluoro-
methyl)phenyl]piperazine (0.21 g, 0.91 mmol), and potassium
carbonate (0.21 g, 1.5 mmol) was heated in 10 mL of refluxing
acetonitrile for 18 h. The reaction was diluted with methylene
chloride and filtered, and the solvents were removed under
reduced pressure. The residue was partitioned between
chloroform and 2 N Na2CO3. The organic layer was dried over
sodium sulfate and evaporated. The resulting residue was
recrystallized from acetonitrile to give the product as a white
solid (0.33 g, 83% yield). Mp 166-7 °C; 1H NMR (400 MHz,
CDCl3) δ 8.21 (d, J ) 6 Hz, 2 H), 7.29 (t, J ) 8 Hz, 2 H), 7.03
(m, 3 H), 6.44 (t, J ) 5 Hz, 1 H), 4.95 (d, J ) 8 Hz, 1 H), 3.71
(m, 1 H), 3.21 (br s, 4 H), 2.56 (br s, 4 H), 2.39 (t, J ) 8 Hz, 2
H), 2.08 (d, J ) 9 Hz, 2 H), 1.77 (d, J ) 11 Hz, 2 H), 1.42 (m,
2 H), 1.26 (m, 1 H), 1.13 (m, 4 H); CIMS m/z 434 (M + H,
base). Anal. (C22H30F3N5) C, H, N, F.
J ) 5 Hz, 2 H), 6.96 (d, 1 H), 6.90 (m, 2 H), 6.81 (d, J ) 8 Hz,
1 H), 6.44 (t, J ) 5 Hz, 1 H), 4.93 (d, J ) 8 Hz, 1 H), 3.82 (s,
3 H), 3.72 (m, 1 H), 3.07 (brs, 4 H), 2.62 (brs, 4 H), 2.41 (t, J
) 8 Hz, 2 H), 2.08 (d, J ) 9 Hz, 2 H), 1.78 (d, J ) 9 Hz, 2 H),
1.43 (dt, J ) 8, 7 Hz, 2 H), 1.27 (m, 2H), 1.24-1.09 (m, 4 H);
CIMS (396 M + H, base). Anal. (C23H33N5O) C, H, N.
tr a n s-(4-{2-[4-(4-Meth oxyp h en yl)p ip er a zin -1-yl]eth yl}-
cycloh exyl)p yr im id in -2-yla m in e (40). Mp 177-8 °C (ethyl
acetate); 1H NMR (CDCl3, 400 MHz) δ 8.21 (d, J ) 5 Hz, 2 H),
6.86 (d, J ) 9 Hz, 2 H), 6.79 (d, J ) 9 Hz, 2 H), 6.44 (t, J ) 5
Hz, 1 H), 4.96 (d, J ) 8 Hz, 1 H), 3.72 (s, 3 H), 3.07 (t, J ) 5
Hz, 4 H), 2.58 (t, J ) 5 Hz, 4 H), 2.38 (t, J ) 8 Hz, 2 H), 2.08
(d, J ) 9 Hz, 2 H), 1.78 (d, J ) 10 Hz, 2 H), 1.43 (dt, J ) 8, 7
Hz, 2 H), 1.26 (m, 2H), 1.20-1.05 (m, 4 H); CIMS m/e 396 (M
+ H, base). Anal. (C23H33N5O) C, H, N.
tr a n s-(4-{2-[4-(4-F lu or op h en yl)p ip er a zin -1-yl]et h yl}-
cycloh exyl)p yr im id in -2-yla m in e (42). A mixture of 4-[(2-
bromoethyl)cyclohexyl]pyrimidin-2-ylamine (0.47 g, 1.64 mmol),
1-(4-fluorophenyl)piperazine (0.31 g, 1.70 mmol), and potas-
sium carbonate (0.31 g, 2 mmol) was heated under reflux in
acetonitrile (40 mL) for 18 h. After the reaction mixture was
cooled, the salts were filtered off and the filtrate was concen-
trated to an oily solid. The residue was partitioned between
chloroform (∼100 mL) and dilute Na2CO3 (∼100 mL), and the
organic layer was dried (K2CO3) and then concentrated in
vacuo to provide a solid. This was recrystallized in ethyl
acetate (∼30 mL) to provide the title compound 42 (0.33 g,
51%). Mp 162-163 °C; 1H NMR (CDCl3, 400 MHz) δ 8.21 (d,
J ) 5 Hz, 2 H), 6.95 (m, 2 H), 6.84 (m, 2 H), 6.42 (m, 1H), 4.87
(d, J ) 11 Hz, 1 H), 3.7 (m, 1 H), 3.1(s, 4 H), 2.6 (s, 4 H), 2.4
(m, 2 H), 2.1 (m, 2 H), 1.8 (m, 2 H), 1.5 (s, 2 H) 1.42 (q, J ) 10
Hz, 2 H), 1.35 (br s, 1 H), 1.1 (m, 4 H); CIMS (384 M + H,
base). Anal. (C22H30N5F) C, H, N, F.
t r a n s -{4-[2-(4-P y r i d i n -2-y lp i p e r a z i n -1-y l)e t h y l]-
cycloh exyl}p yr im id in -2-yla m in e (43). Mp 138-140 °C
(EtOH); 1H NMR (CDCl3, 400 MHz) δ 8.19 (d, J ) 5 Hz, 2 H),
8.14 (d, J ) 5 Hz, 1 H), 7.42 (t, J ) 8 Hz, 1 H), 6.59(d, J ) 8
Hz, 1 H), 6.56(t, J ) 8 Hz, 1 H), 6.43 (d, J ) 5 Hz, 1 H), 4.98
(d, J ) 8 Hz, 1 H), 3.70 (m, 1H), 3.51 (t, J ) 5 Hz, 4 H), 2.50
(t, J ) 5 Hz, 4 H), 2.36 (t, J ) 6 Hz, 2 H), 2.06 (dd, J ) 9, 1
Hz, 2H), 1.78 (dd, J ) 9, 1 Hz, 2H), 1.42 (dt, J ) 8, 8 Hz, 2 H),
1.26 (m 1 H), 1.21-1.07 (m, 4 H); CIMS 367 (M + H, base).
Anal. (C21H30N6) C, H, N.
t r a n s {4-[2-(4-P y r i d i n -3-y lp i p e r a z i n -1-y l)e t h y l]-
cycloh exyl}p yr im id in -2-yla m in e (44). Mp 174-5 °C; 1H
NMR (CDCl3, 400 MHz) δ 8.27 (d, J ) 2 Hz, 1 H), 8.20 (d, J )
5 Hz, 2 H), 8.05 (dd, J ) 4., 2 Hz, 1 H), 7.12 (m, 2 H), 6.44 (t,
J ) 5 Hz, 1 H), 4.92 (d, J ) 8 Hz, 1 H), 3.71 (m, 1H), 3.20 (t,
J ) 5 Hz, 4 H), 2.57 (t, J ) 5 Hz, 4 H), 2.38 (t, J ) 6 Hz, 2 H),
2.08 (d, J ) 10 Hz, 2 H), 1.78 (d, J ) 10 Hz, 2 H), 1.42 (dd, J
) 15, 7 Hz, 2 H), 1.28 (m, 1 H), 1.21-1.07 (m, 4 H); CIMS 367
(M + H, base). Anal. (C21H30N6) C, H, N.
t r a n s -{4-[2-(4-P y r i d i n -4-y lp i p e r a z i n -1-y l)e t h y l]-
cycloh exyl}p yr im id in -2-yla m in e (45). Mp 199-200 °C; 1H
NMR (CDCl3, 400 MHz) δ 8.21 (m, 4 H), 6.61 (d, J ) 5 Hz, 2
H), 6.44 (t, J ) 5 Hz, 1 H), 4.92 (d, J ) 8 Hz, 1 H), 3.71 (m,
1H), 3.29 (t, J ) 5 Hz, 4 H), 2.51 (t, J ) 5 Hz, 4 H), 2.36 (t, J
) 6 Hz, 2 H), 2.08 (d, J ) 10 Hz, 2 H), 1.77 (d, J ) 10 Hz, 2
H), 1.41 (dd, J ) 15, 7 Hz, 2 H), 1.26 (m, 1 H), 1.21-1.07 (m,
4 H); CIMS 367 (M + H, base). Anal. (C21H30N6) C, H, N.
P yr im id in -2-yl-{4-[2-(4-p yr im id in -2-ylp ip er a zin -1-yl)-
eth yl]cycloh exyl}a m in e (46). Mp 154-155 °C; 1H NMR
(400 MHz, CDCl3) δ 8.25 (2H, m), 8.2 (2H, m), 6.4 (2H, m), 4.9
(1H, d, J ) 11 Hz), 3.8 (4H, m), 3.76 (1H, m), 2.45 (4H, m),
2.38 (2H, m), 2.08 (2H, m), 1.75 (2H, m), 1.4 (2H, m), 1.35 (1H,
br s),1.05 (4H, m); MS (CI/NH3) m/z 368 (M + H). Anal.
(C20H29N7) C, H, N.
tr a n s-P yr im id in -2-yl-{4-[2-(2,3,5,6-tetr a h yd r o-[1,2′]bi-
p yr a zin yl-4-yl)eth yl]cycloh exyl}a m in e (47). Mp 162-163;
1H NMR (CDCl3, 400 MHz) δ 8.19 (d, J ) 2 Hz, 1 H), 8.07 (d,
J ) 1 Hz, 1 H), 7.99 (dd, J ) 1, 3 Hz, 1 H), 7.77 (d, J ) 3 Hz,
1 H), 6.42 (t, J ) 5 Hz, 1 H), 4.92 (d, J ) 8 Hz, 1 H), 3.68 (m,
1H), 3.54 (t, J ) 5 Hz, 4 H), 2.48 (t, J ) 5 Hz, 4 H), 2.37 (t, J
) 7 Hz, 2 H), 2.05 (d, J ) 10 Hz, 2 H), 1.75 (d, J ) 10 Hz, 2
In a similar way the following compounds were prepared
from bromide 33 using the appropriate amine.
tr a n s-{4-[2-(4-P h en yl-3,6-dih ydr o-2H-pyr idin -1-yl)eth yl]-
cycloh exyl}p yr im id in -2-yla m in e (34). Mp 146-147 °C; 1H
NMR (400 MHz, CDCl3) δ 8.2(d, J ) 5 Hz, 2 H), 7.35 (m, 2 H),
7.15 (m, 2 H), 7.10 (m, 2 H) 6.45 (t, J ) 4 Hz 1 H), 6.0 (s, 1 H),
4.90 (d, J ) 11 Hz, 1 H), 3.15 (br s, 2 H), 2.70 (br s, 2 H), 2.55
(br s, 2H), 2.45 (br s, 2H), 2.05 (m, 2 H), 1.80 (m, 2H), 1.30 (br
s, 1H) 1.05 (m, 4H); CIMS 362 (M + H, base). Anal.
(C23H30N4‚0.5H2O) C, H, N.
tr a n s-{4-[2-(3,4-Dih yd r o-1H -isoq u in olin -2-yl)et h yl]-
cycloh exyl}p yr im id in -2-yla m in e (35). Mp 125-126 °C
(acetonitrile); 1H NMR (CDCl3, 400 MHz) δ 8.22 (d, J ) 5 Hz,
2 H), 7.07 (m, 3 H), 6.99 (d, J ) 5 Hz 1 H), 4.93 (d, J ) 8 Hz,
1 H), 3.73 (m, 1 H), 3.60 (s, 2 H), 2.88 (m, 2H),6.44 (t, J ) 5
Hz, 1 H), 2.71 (br s, 2 H), 2.52 (t, J ) 8 Hz, 2 H) 2.08 (m, 2H),
1.82 (m, 2H), 1.51 (dt, J ) 8, 7 Hz, 2 H), 1.31 (m 1 H), 1.21-
1.07 (m, 4 H); CIMS 337 (M + H, base). Anal. (C21H28N4) C,
H, N.
tr a n s-{4-[2-[(Meth ylph en eth yl)am in o]eth yl]cycloh exyl}-
p yr im id in -2-yla m in e (36). Mp 68-9 °C (acetonitrile); 1H
NMR (CDCl3, 400 MHz) δ 8.20 (d, J ) 5 Hz, 2 H), 7.24 (t, J )
8 Hz, 2H), 7.15 (m, 3H), 6.43 (t, J ) 5 Hz, 1 H), 4.97 (m, 1 H),
3.70 (m, 1H), 2.73 (dd J ) 9, 8 Hz, 2H), 2.55 (dd J ) 9, 8 Hz,
2H), 2.38 (t, J ) 8 Hz, 2H), 2.25 (s, 3H), 2.06 (d, J ) 11 Hz, 2
H), 1.74 d, J ) 11 Hz, 2 H), 1.36 (dd, J ) 11, 7 Hz, 2 H), 1.24
(m, 1 H), 1.21-1.07 (m, 4 H); CIMS (339, M + H, 80%). Anal.
(C21H30N4) C, H, N.
tr a n s-[4-(2-Dipr opylam in oeth yl)cycloh exyl]pyr im idin -
2-yla m in e (37). Mp 71-72 °C; 1H NMR (CDCl3, 400 MHz) δ
8.21 (d, J ) 5 Hz, 2 H), 6.44 (t, J ) 5 Hz, 1 H), 4.90 (d, J ) 8
Hz, 1 H), 3.70 (m, 1 H), 2.42 (m, 2 H), 2.35 (m, 4 H), 2.07 (d,
J ) 9 Hz, 2 H), 1.75 (d, J ) 9 Hz, 2 H), 1.43 (m, 4 H), 1.34 (m,
2 H), 1.26 (m, 1 H), 1.21-1.07 (m, 4 H); CIMS (305, M + H,
base). Anal. (C18H32N4) C, H, N.
tr a n s-(4-{2-[4-(2,3-Dich lor oph en yl)piper azin -1-yl]eth yl}-
cycloh exyl)p yr im id in -2-yla m in e (38). Mp 169-170 °C
1
(ethyl acetate); H NMR (CDCl3, 400 MHz) δ 8.26 (d, J ) 5
Hz, 2 H), 7.15 (m, 2 H), 6.96 (dd, J ) 3, 6 Hz, 1H), 6.48 (t, J
) 5 Hz, 1 H), 4.98 (d, J ) 8 Hz, 1 H), 3.75 (m, 1H), 3.07 (m, 4
H), 2.64 (m, 4 H), 2.44 (t, J ) 8 Hz, 2 H), 2.13 (d, J ) 9 Hz, 2
H), 1.82 (d, J ) 9 Hz, 2 H), 1.46 (dt, J ) 8, 7 Hz, 2 H), 1.32 (m,
2H), 1.24-1.09 (m, 4 H) CIMS (434 M + H, base). Anal.
(C22H29N5Cl2) C, H, N, Cl.
tr a n s-(4-{2-[4-(2-Meth oxyp h en yl)p ip er a zin -1-yl]eth yl}-
cycloh exyl)p yr im id in -2-yla m in e (39). Mp 138-139 °C
(hexane, ethyl acetate); 1H NMR (CDCl3, 400 MHz) δ 8.21 (d,