Novel Dopamine D3 Receptor Ligands
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 19 3183
7.08-7.17 (m, 2H), 7.31-7.41 (m, 3H), 7.57 (t, J ) 8.0 Hz, 2H),
7.79 (d, J ) 6.9 Hz, 1H), 7.87 (d, J ) 7.5 Hz, 1H); 13C NMR δ
24.6, 29.7, 37.7, 40.3, 51.2, 53.4, 58.1, 118.5, 119.9, 122.1, 124.7,
124.8, 125.0, 126.7, 126.9, 127.3, 127.4, 132.2, 134.0, 140.5,
142.9, 143.2, 143.8, 151.0, 168.0; IR (KBr pellet) 751, 780, 957,
1277, 1455, 1522, 1579, 1636, 2598, 2929, 3384 cm-1. Anal.
(C27H27Cl2N3O‚HCl) C, H, N.
(q, J ) 5.9 Hz, 2H), 4.81 (s, 1H), 6.07 (bs, 1H), 6.87-6.90 (m,
1H), 7.15-7.18 (m, 2H), 7.33-7.44 (m, 4H), 7.68-7.75 (m, 4H);
13C NMR δ 25.3, 38.9, 50.1, 53.2, 56.3, 56.6, 118.6, 120.2, 124.5,
125.3, 127.3, 127.4, 127.7, 128.3, 134.0, 141.4, 141.8, 151.1,
170.7. Anal. (C27H27Cl2N3O‚HCl‚0.25H2O) C, H, N.
N-{4-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]bu tyl}flu -
or en -9-ylca r boxa m id e (47). Using general procedure B with
9-fluorenecarboxylic acid (44) gave the corresponding acid
chloride, which was converted to the desired product as an
oil, using general procedure C with amine 33. Column chro-
matography (95% CMA, Rf 0.5) followed by treatment with
HCl-saturated MeOH and crystallization from 2-PrOH gave
0.25 g (48%) of 47 as the HCl salt: mp 210-212 °C; 1H NMR
δ 1.34-1.38 (m, 4H), 2.29 (t, J ) 6.8 Hz, 2H), 2.49 (bs, 4H),
2.98 (bs, 4H), 3.16 (q, J ) 6.3 Hz, 2H), 4.80 (s, 1H), 5.33 (bs,
1H), 6.90-6.93 (m, 1H), 7.10-7.16 (m, 2H), 7.35 (dt, J ) 1.3,
7.2 Hz, 2H), 7.44 (t, 2H), 7.69 (d, J ) 7.7 Hz, 2H), 7.78 (d, J )
7.3 Hz, 2H); 13C NMR δ 23.7, 27.3, 39.2, 39.4, 51.2, 53.1, 56.2,
57.9, 118.6, 120.3, 124.5, 125.3, 127.4, 127.5, 127.7, 128.3,
134.0, 141.3, 141.4, 141.6, 151.2, 170.6. Anal. (C28H29Cl2N3O‚
HCl‚0.5H2O) C, H, N.
F lu or en -2-yl-N-[3-(4-p h en ylp ip er a zin -1-yl)p r op yl]ca r -
boxa m id e (43a ). J ones reagent was added dropwise to a
solution of 2-fluorenecarboxaldehyde (41, 1.0 g, 5 mmol) in
acetone (10 mL) until a persistent orange color was observed.
After 10 min, the reaction was quenched by dropwise addition
of 2-PrOH. The reaction mixture was diluted with ether (50
mL), followed by H2O (10 mL), to dissolve the inorganic
residue. Following removal of the ethereal phase, the aqueous
phase was re-extracted with ether (50 mL). The combined
ether extracts were washed with H2O (1 × 50 mL) and brine
(1 × 50 mL) and dried (MgSO4). The solvent was removed in
vacuo to give compound 42 as an oil, which crystallized on
standing. Using general procedure B with 42 gave the corre-
sponding acid chloride, which was converted to the desired
product (43a ) that was isolated as an oil using general
procedure C with amine 30a . Column chromatography (95%
CMA, Rf 0.3) followed by treatment with HCl-saturated MeOH
and crystallization from MeOH gave 1.98 g (92% over three
steps) of 42 as the HCl salt: mp 257-259 °C; 1H NMR δ 1.84-
1.87 (m, 2H), 2.64-2.70 (m, 6H), 3.23 (t, J ) 4.8 Hz, 4H), 3.61-
3.66 (m, 2H), 3.73 (s, 2H), 6.87-6.91 (m, 3H), 7.22-7.40 (m,
4H), 7.45 (d, J ) 7.2 Hz, 1H), 7.75 (t, J ) 8.0 Hz, 2H), 7.86 (d,
J ) 8.0 Hz, 1H), 7.99 (s, 1H), 8.35 (bs, 1H); 13C NMR δ 24.4,
36.7, 40.8, 49.3, 53.4, 58.5, 116.1, 119.7, 120.1, 120.5, 123.6,
125.1, 126.0, 126.9, 127.5, 129.1, 132.9, 140.6, 143.2, 144.0,
144.7, 151.2, 167.5; IR (KBr pellet) 693, 752, 1314, 1454, 1532,
1634, 2581, 2924, 3256 cm-1. Anal. (C27H29N3O‚HCl) C, H, N.
N-{3-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]p r op yl}-
flu or en -2-ylca r boxa m id e (43b). Using general procedure B
with 2-fluorenecarboxylic acid (42) gave the corresponding acid
chloride that was converted to the desired product 43b as an
oil, using general procedure C with amine 30b. Column
chromatography (95% CMA, Rf 0.4) followed by treatment with
HCl saturated MeOH and crystallization from 2-PrOH gave
1.63 g (63% over three steps) of 43b as the HCl salt: mp 233-
235 °C; 1H NMR δ 1.80-1.88 (m, 2H), 2.65-2.69 (m, 6H), 3.01
(s, 4H), 3.61-3.66 (m, 2H), 3.87 (s, 2H), 6.73 (d, J ) 8.0 Hz,
1H), 6.94 (t, J ) 8.0 Hz, 1H), 7.13 (dd, J ) 1.2, 8.1 Hz, 1H),
7.32-7.43 (m, 2H), 7.52 (d, J ) 7.2 Hz, 1H), 7.77-7.87 (m,
3H), 8.01(s, 1H), 8.35 (s, 1H); 13C NMR δ 24.5, 36.9, 40.7, 51.2,
53.4, 58.3, 118.3, 119.6, 120.4, 123.8, 124.8, 125.2, 126.1, 127.0,
127.3, 127.5, 127.6, 133.4, 134.1, 140.7, 143.2, 143.9, 144.6,
150.9, 167.7. Anal. (C27H27Cl2N3O‚HCl) C, H, N.
F lu or en -9-yl-N-[3-(4-p h en ylp ip er a zin -1yl)p r op yl]ca r -
boxa m id e (45). Using general procedure B with 9-fluorene-
carboxylic acid (44) gave the corresponding acid chloride, which
was converted to the desired product (oil) using general
procedure C with amine 30a . Column chromatography (95%
CMA, Rf 0.3) followed by treatment with HCl-saturated MeOH
and crystallization from acetone/hexane gave 1.52 g (37%) of
45 as the HCl salt: mp 226-228 °C; 1H NMR δ 1.52-1.62 (m,
2H), 2.26 (t, J ) 6.5 Hz, 2H), 2.34 (bs, 4H), 2.83 (bs, 4H), 3.29
(q, J ) 5.6 Hz, 2H), 4.79 (s, 1H), 6.21 (bs, 1H), 6.84-6.90 (m,
3H), 7.26-7.39 (m, 7H), 7.64-7.69 (m, 3H); 13C NMR δ 25.1,
39.1, 48.4, 53.1, 56.3, 56.9, 115.8, 119.5, 120.3, 126.2, 127.7,
128.3, 129.0, 141.3, 141.7, 141.8, 151.1, 170.7; IR (KBr pellet)
690, 740, 1239, 1446, 1627, 2382, 2819, 2944 cm-1. Anal.
(C27H29N3O‚HCl) C, H, N.
N-{3-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]p r op yl}-
flu or en -9-ylca r boxa m id e (46) Using general procedure B
with 9-fluorenecarboxylic acid (44) gave the corresponding acid
chloride, which was converted to the desired product (oil) using
general procedure C with amine 30b. Column chromatography
(95% CMA, Rf 0.4) followed by treatment with HCl-saturated
MeOH and crystallization from 2-PrOH gave 0.77 g (50%) of
46 as the HCl salt: mp 214-216 °C; 1H NMR δ 1.51-1.59 (m,
2H), 2.26 (t, J ) 6.5 Hz, 2H), 2.35 (bs, 4H), 2.72 (bs, 4H), 3.28
(9-Oxoflu or en -4-yl)-N-[3-(4-p h en ylp ip er a zin -1-yl)p r o-
p yl]ca r boxa m id e (49). Using general procedure C with
9-fluorenone-4-carbonyl chloride (48) and amine 30a gave
product 49 as an oil. Column chromatography (95% CMA, Rf
0.3) followed by treatment with HCl-saturated MeOH and
crystallization from 2-PrOH gave 0.87 g (47%) of 49 as the
HCl salt: mp 213-215 °C; 1H NMR δ 1.80-1.88 (m, 2H), 2.52-
2.60 (m, 6H), 2.91 (t, J ) 4.7 Hz, 4H), 3.62 (q, J ) 5.7 Hz 2H),
6.76 (d, J ) 8.1 Hz, 2H), 6.85 (t, J ) 7.3 Hz, 1H), 7.15-7.31
(m, 4H), 7.43-7.47 (m, 2H), 7.57 (d, J ) 7.3 Hz, 1H), 7.63 (d,
J ) 7.2 Hz, 1H), 7.80 (d, J ) 7.7 Hz, 1H), 8.22 (bs, 1H); 13C δ
24.5, 40.4, 49.1, 53.1, 57.6, 116.1, 120.0, 124.0, 124.1, 125.2,
128.8, 129.0, 129.4, 132.4, 132.9, 134.1, 134.8, 134.9, 140.9,
143.0, 150.9, 168.0, 192.8; IR (KBr pellet) 733, 1239, 1445,
1593, 1601, 1637, 1717, 2822, 2940, 3281 cm-1. Anal. (C27H27
-
N3O2‚HCl‚0.75H2O) C, H, N.
N-{3-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]p r op yl}(9-
oxoflu or en -4-yl)ca r boxa m id e (50). Using general procedure
C with 9-fluorenone-4-carbonyl chloride (48) and amine 30b
gave product 50 as an oil. Column chromatography (95% CMA,
Rf 0.3) followed by treatment with HCl-saturated MeOH and
crystallization from MeOH gave 2.29 g (83%) of 50 as the HCl
salt: mp 275-278 °C; 1H NMR δ 1.84-1.88 (m, 2H), 2.57-
2.70 (m, 10H), 3.68 (t, J ) 5.9 Hz, 2H), 6.59 (d, J ) 7.4 Hz,
1H), 7.09-7.17 (m, 2H), 7.27-7.35 (m, 2H), 7.47-7.56 (m, 2H),
7.68-7.72 (m, 2H), 7.85 (d, J ) 7.6 Hz, 1H); 13C NMR δ 24.1,
40.8, 51.1, 53.1, 57.9, 118.3, 124.1, 124.4, 124.9, 125.3, 127.5,
129.0, 129.6, 132.7 133.2, 134.0, 134.9, 135.0, 140.9, 143.2,
150.7, 167.9, 192.9; IR (KBr pellet) 737, 954, 1256, 1444, 1535,
1664, 1711, 2414, 2839, 2955, 3348 cm-1. Anal. (C27H25Cl2N3O2‚
HCl‚0.75H2O) C, H, N.
N-{4-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]b u t yl}(9-
oxoflu or en -4-yl)ca r boxa m id e (51). Using general procedure
C with 9-fluorenone-4-carbonyl chloride (48) and amine 33
gave carboxamide 51 as an oil. Column chromatography (95%
CMA, Rf 0.4) followed by treatment with HCl-saturated MeOH
and crystallization from 2-PrOH gave 0.35 g (64%) of 51 as
the HCl salt: mp 185-187 °C; 1H NMR δ 1.69-1.80 (m, 4H),
2.43 (t, J ) 6.5 Hz, 2H), 2.51 (bs, 4H), 2.71 (bs, 4H), 3.56 (q,
J ) 5.6 Hz, 2H), 6.57-6.61 (m, 1H), 7.05-7.16 (m, 2H), 7.25-
7.33 (m, 2H), 7.47 (t, J ) 7.7 Hz, 2H), 7.65 (d, J ) 7.4 Hz,
2H), 7.75 (d, J ) 7.6 Hz, 1H), 8.08 (bs, 1H); 13C NMR δ 24.6,
27.5, 39.8, 50.8, 53.1, 57.8, 118.3, 123.7, 124.3, 124.7, 125.2,
127.4, 129.0, 129.5, 132.7, 133.0, 133.9, 134.1, 134.8, 135.1,
140.9, 143.0, 150.7, 168.2, 192.9. Anal. (C28H27Cl2N3O2‚HCl‚
0.75H2O) C, H, N.
N-{5-[4-(2,3-Dich lor op h en yl)p ip er a zin -1-yl]p en tyl}(9-
oxoflu or en -4-yl)ca r boxa m id e (52). Using general procedure
C with 9-fluorenone-4-carbonyl chloride (48) and amine 38
gave carboxamide 52 as an oil. Column chromatography (95%
CMA, Rf 0.4) followed by treatment with HCl-saturated MeOH
and crystallization from 2-PrOH gave 0.23 g (43%) of 52 as
the HCl salt: mp 244-246 °C; 1H NMR δ 1.40-1.67 (m, 6H),