SAR of a Selective D4 Receptor Ligand
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 2 275
overnight. After cooling, the mixture was evaporated to
dryness, and 20% aqueous Na2CO3 was added to the residue.
The aqueous phase was extracted two times with CH2Cl2, and
the collected organic layers were dried over Na2SO4 and were
evaporated under reduced pressure. The crude residue was
chromatographed as indicated below to give title compounds.
4-[4-(4-Ch lor oph en yl)-piper azin -1-yl]-1-(3-m eth oxyph en -
yl)-1-bu ta n on e (28). Eluted with CHCl3/AcOEt, 7:3; 40%
mL), under stirring. After being refluxed for 1 h, the reaction
mixture was cooled at -10 °C and MeOH was added very
carefully dropwise until gas evolution ceased. The mixture was
treated with 3 N HCl (5 mL) and was refluxed for 1 h. After
cooling, the mixture was alkalized with 3 N NaOH and
extracted with CH2Cl2 (2 × 50 mL). The collected organic
layers were dried over Na2SO4, and the solvent was evaporated
under reduced pressure to give the amine 19 as a white
semisolid in nearly quantitative yield. 1H NMR (90 MHz):
1.25-1.75 [m, 6H, (CH2)3CH2NH2], 2.00 (br s, 2H, NH2, D2O
exchanged), 2.25-2.90 [m, 8H, CH2N(CH2)2, CH2NH2], 3.05-
3.33 [m, 4H, ArN(CH2)2], 6.75-7.35 (m, 4H, aromatic). GC/
MS: m/z 283 (M+ + 2, 2), 282 (M+ + 1, 3), 281 (M+, 6), 268
(20), 266 (58), 211 (34), 209 (100), 195 (28), 166 (45), 141 (71),
98 (71).
Gen er a l P r oced u r e for P r ep a r a tion of th e Ben za -
m id es 33-35. To a cooled mixture containing amines 17-19
(5.0 mmol) and a slight excess of NaHCO3 was added dropwise
a solution of 3-methoxybenzoyl chloride, prepared from 3-meth-
oxybenzoic acid (2.00 g, 11 mmol) in SOCl2 (5 mL), in CH2Cl2
(50 mL) under vigorous stirring. Then the aqueous layer was
separated and extracted with CH2Cl2. The organic layer was
dried over Na2SO4 and evaporated to dryness under reduced
pressure. Final compounds were purified by column chroma-
tography (CHCl3/MeOH, 19:1 as eluent) to give benzamides
33-35 in 90-95% yield.
N-[3-[4-(4-Ch lor oph en yl)piper azin -1-yl]pr opyl]-3-m eth -
oxyben za m id e (33). 1H NMR: 1.75-1.85 (m, 2H, CH2CH2-
CH2), 2.59-2.66 [m, 6H, CH2N(CH2)2], 3.14 [br t, 4H, (CH2)2-
NAr], 3.56 (q, 2H, J ) 5.5 Hz, NHCH2), 3.72 (s, 3H, CH3),
6.77-7.44 (m, 8H, aromatic), 8.11 (br s, 1H, NH, D2O ex-
changed). GC/MS: m/z 389 (M+ + 2, 7), 388 (M+ + 1, 5), 387
(M+, 20), 372 (34), 221 (100), 209 (54), 192 (56), 135 (56).
N-[4-[4-(4-Ch lor op h en yl)p ip er a zin -1-yl]bu tyl]-3-m eth -
oxyben za m id e (34). 1H NMR: 1.70-1.75 [m, 4H, CH2(CH2)2-
CH2], 2.57 [br s, 2H, CH2N(CH2)2], 2.72 [br t, 4H, CH2N(CH2)2],
3.21 [br t, 4H, (CH2)2NAr], 3.44-3.49 (m, 2H, NHCH2), 3.81
(s, 3H, CH3), 6.77-7.34 (m, 9H, aromatic, NH). GC/MS: m/z
403 (M+ + 2, 4), 402 (M+ + 1, 4), 401 (M+, 11), 386 (20), 235
(100), 209 (57), 135 (51).
1
yield. H NMR: 1.92-2.02 (m, 2H, CH2CH2CH2), 2.46 [t, 2H,
J ) 7.1, CH2N(CH2)2], 2.58 [br t, 4H, CH2N(CH2)2], 3.00 (t,
2H, J ) 7.0 Hz, COCH2), 3.10 [br t, 4H, (CH2)2NAr], 3.82 (s,
3H, CH3), 6.77-7.55 (m, 8H, aromatic). GC/MS: m/z 374 (M+
+ 2, 14), 373 (M+ + 1, 10), 372 (M+, 39), 224 (36), 222 (100),
211 (30), 209 (91), 177 (31), 166 (56), 135 (32).
1-(4-Ch lor op h en yl)-4-[4-(3-m eth oxyp h en yl)bu tyl]p ip -
er a zin e (29). Eluted with CHCl3/AcOEt, 7:3; 36% yield. 1H
NMR: 1.50-1.70 [m, 4H, CH2(CH2)2CH2], 2.40 [t, 2H, J ) 7.4
Hz, CH2N(CH2)2], 2.55-2.63 [m, 6H, ArCH2, CH2N(CH2)2], 3.15
[br s, 4H, (CH2)2NAr], 3.78 (s, 3H, CH3), 6.69-7.24 (m, 8H,
aromatic). GC/MS: m/z 360 (M+ + 2, 17), 359 (M+ + 1, 12),
358 (M+, 47), 211 (35), 209 (100).
3-(4-Ch lor op h en yl)-N-(3-m et h oxyp h en yl)-1-p ip er a zi-
n op r op a n a m id e (31). Eluted with CHCl3/AcOEt, 1:1; 75%
yield. 1H NMR: 2.53-2.57 [m, 2H, CH2N(CH2)2], 2.73-2.79 [m,
6H, CH2CH2N(CH2)2], 3.25 [br t, 4H, (CH2)2NAr], 3.76 (s, 3H,
CH3), 6.58-7.35 (m, 8H, aromatic), 10.72 (br s, 1H, NH, D2O
exchanged). GC/MS: m/z 196 (31), 177 (38), 156 (28), 154 (100),
123 (41).
5-[4-(4-Ch lor oph en yl)-piper azin -1-yl]-1-(3-m eth oxyph en -
yl)-1-p en ta n on e (36). Eluted with CHCl3/AcOEt, 7:3; 56%
1
yield. H NMR: 1.56-1.66 (m, 2H, CH2CH2N), 1.72-1.82 (m,
2H, COCH2CH2), 2.43 [br t, 2H, CH2N(CH2)2], 2.59 [br t, 4H,
CH2N(CH2)2], 2.98 (t, 2H, J ) 7.2 Hz, COCH2), 3.15 [br t, 4H,
(CH2)2NAr], 3.83 (s, 3H, CH3), 6.79-7.54 (m, 8H, aromatic).
GC/MS: m/z 388 (M+ + 2, 13), 387 (M+ + 1, 10), 386 (M+, 38),
211 (34), 209 (100).
6-[4-(4-Ch lor oph en yl)-piper azin -1-yl]-1-(3-m eth oxyph en -
yl)-1-h exa n on e (37). Eluted with CH2Cl2/AcOEt, 7:3; 23%
1
yield. H NMR: 1.37-1.45 [m, 2H, CH2(CH2)2], 1.53-1.63 (m,
2H, CH2CH2N), 1.70-1.80 (m, 2H, COCH2CH2), 2.40 [br t, 2H,
CH2N(CH2)2], 2.59 [br t, 4H, CH2N(CH2)2], 2.95 (t, 2H, J )
7.3 Hz, COCH2), 3.16 [br t, 4H, (CH2)2NAr], 3.83 (s, 3H, CH3),
6.79-7.53 (m, 8H, aromatic). GC/MS: m/z 402 (M+ + 2, 12),
401 (M+ + 1, 10), 400 (M+, 35), 211 (35), 209 (100), 177 (31),
166 (56), 135 (32).
N-[5-[4-(4-Ch lor oph en yl)piper azin -1-yl]pen tyl]-3-m eth -
oxyben za m id e (35). 1H NMR: 1.38-1.46 [m, 2H, (CH2)2CH2-
(CH2)2] 1.54-1.68 (m, 4H, CH2CH2CH2CH2CH2), 2.43 [br t, 2H,
CH2N(CH2)2], 2.61 [br t, 4H, CH2N(CH2)2], 3.16 [br t, 4H,
(CH2)2NAr], 3.43 (q, 2H, J ) 5.0, NHCH2), 3.81 (s, 3H, CH3),
6.21 (br s, 1H, NH, D2O exchanged), 6.78-7.34 (m, 8H,
aromatic). GC/MS: m/z 417 (M+ + 2, 5), 416 (M+ + 1, 4), 415
(M+, 14), 400 (20), 249 (100), 211 (26), 209 (77), 135 (44).
1-(4-Ch lor op h en yl)-4-[3-(1,2,3,4-tetr a h yd r o-5-m eth oxy-
1-n aph th alen yl)pr opyl]piper azin e (40). Eluted with CHCl3/
AcOEt, 1:1; 81% yield. 1H NMR: 1.54-1.84 [m, 8H, CH-
(CH2CH2)2], 2.40 [br t, 2H, CH2N(CH2)2], 2.52-2.77 [m, 7H,
benzylic CH2 and CH, CH2N(CH2)2], 3.16 (br t, 4H, (CH2)2NAr],
3.79 (s, 3H, CH3), 6.63-7.24 (m, 7H, aromatic). GC/MS: m/z
400 (M+ + 2, 27), 399 (M+ + 1, 22), 398 (M+, 77), 210 (36), 209
(100), 196 (40).
4-(4-Ch lor op h en yl)-N-[(3-m et h oxyp h en yl)m et h yl]-1-
p ip er a zin eeth a n a m in e (30). This compound was obtained
in nearly quantitative yield from the reduction of benzamide
1 with borane methyl sulfide complex, following the procedure
1
reported for the compound 19. H NMR: 2.06 (br s, 1H, NH,
1-(4-Ch lor op h en yl)-4-[3-(1,2,3,4-tetr a h yd r o-7-m eth oxy-
1-n a p h th a len yl)p r op yl]p ip er a zin e (41). Eluted with CH2-
Cl2/AcOEt, 4:1; 95% yield. 1H NMR: 1.57-1.88 [m, 8H,
CH(CH2CH2)2], 2.41 [br t, 2H, CH2N(CH2)2], 2.59-2.74 [m, 7H,
benzylic CH2 and CH, CH2N(CH2)2], 3.16 (br t, 4H, (CH2)2NAr],
3.76 (s, 3H, CH3), 6.63-7.24 (m, 7H, aromatic). GC/MS: m/z
400 (M+ + 2, 11), 399 (M+ + 1, 9), 398 (M+, 33), 211 (33), 209
(100), 196 (37).
4-(4-Ch lor oph en yl)-1-piper azin open tan en itr ile (15). The
title compounds was prepared in 83% yield from the piperazine
14 and 4-chloropentanenitrile following the procedure de-
scribed for the synthesis of the above compounds. 1H NMR
(90 MHz): 1.50-1.85 [m, 4H, (CH2)2CH2CN], 2.20-2.70 [m,
8H, (CH2)2NCH2, CH2CN], 3.00-3.30 [m, 4H, ArN(CH2)2],
6.75-7.35 (m, 4H, aromatic). GC/MS: m/z 279 (M+ + 2, 24),
278 (M+ + 1, 14), 277 (M+, 68), 211 (37), 209 (100), 166 (22),
139 (30), 138 (25).
D2O exchanged), 2.52-2.56 (m, 6H, CH2CH2N(CH2)2], 2.72 [t,
2H, J ) 6.0, CH2N(CH2)2], 3.11 [br t, 4H, (CH2)2NAr], 3.79 (s,
5H, ArCH2, CH3), 6.76-7.25 (m, 8H, aromatic). GC/MS: m/z
361 (M+ + 2, 1), 360 (M+ + 1, 1), 359 (M+, 3), 211 (24), 210
(21), 209 (77), 179 (21), 166 (30), 138 (23), 121 (70), 70 (100).
N -(Me t h o x y c a r b o n y l)-2-(2-m e t h o x y p h e n y l)e t h y l-
a m in e (25). To a solution of 2-methoxyphenetylamine (24)
(5.00 g, 33.1 mmol) and triethylamine (5.5 mL, 39.5 mmol) in
anhydrous THF (50 mL) at 0 °C was carefully added methyl
chloroformate (13.1 mL, 169 mmol). The reaction mixture was
stirred at room temperature for 24 h. H2O was added, the
aqueous and organic layers were separated, and the former
was extracted with Et2O (3 × 20 mL). The combined organic
fractions were washed with 1 N HCl (2 × 50 mL), H2O (50
mL), and brine (50 mL) and dried over Na2SO4. Evaporation
of the solvent in vacuo gave compound 25 in nearly quantita-
1
tive yield. H NMR (90 MHz): 2.80 (t, 2H, J ) 6.0 Hz, CH2-
4-(4-Ch lor op h en yl)-1-p ip er a zin ep en ta n a m in e (19). Bo-
rane-methyl sulfide complex, as 10.0 M BH3 in excess methyl
sulfide (2.0 mL, 20.0 mmol), was dropped into an ice-cooled
solution of nitrile 15 (1.16 g, 4.2 mmol) in anhydrous THF (10
NH), 3.25-3.55 (m, 2H, ArCH2), 3.73 and 3.83 (2 s, 6H, 2 CH3),
4.87 (br s, 1H, NH), 6.75-7.35 (m, 4H, aromatic). GC/MS: m/z
211 (M+ + 2, 1), 210 (M+ + 1, 6), 209 (M+, 40), 134 (100), 122
(26), 121 (52), 119 (37), 91 (80).