New Class of 5-HT7 Receptor Agents
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 26 6621
acetylphenyl)piperazine,38 2-bromo(methylsulfonyl)benzene,39
1-(2-carboxamidophenyl)piperazine,40 1-(4-chloro-2-methoxy-
phenyl)piperazine,41 1-(2-cyanophenyl)piperazine,40 1-(3-cy-
anophenyl)piperazine,42 1-(2,5-dimethoxyphenyl)piperazine,43
5-methoxy-1,2,3,4-tetrahydro-1-naphthalenamine,44 6-meth-
oxy-1,2,3,4-tetrahydro-1-naphthalenamine,45 7-methoxy-1,2,3,4-
tetrahydro-1-naphthalenamine,45 8-methoxy-1,2,3,4-tetrahydro-
1-naphthalenamine,45 1-(2-methylthiophenyl)piperazine,46 1-(2-
nitrophenyl)piperazine,47 2-(1-piperazinyl)-1H-benzimidazole,48
3-(1-piperazinyl)-1,2-benzisoxazole,49 and 2-(1-piperazinyl)-
benzoxazole.50
1-[2-(Methylsulfonyl)phenyl]piperazine (8). A mixture
of 2-bromo(methylsulfonyl)benzene (1.10 g, 4.7 mmol) and
anhydrous piperazine (2.02 g, 23.5 mmol) was heated at 110
°C overnight. Then, the mixture was cooled and partitioned
between 2 N NaOH and CH2Cl2. The separated organic layer
was dried over Na2SO4 and concentrated under reduced
pressure. The crude residue was chromatographed (CHCl3/
CH3OH, 9:1, as eluent) to give 8 as a white semisolid (0.36 g,
34% yield). 1H NMR δ 2.58 (s, 1H, NH, D2O exchanged), 2.84
(s, 4H, piperazinic), 3.14 (s, 3H, CH3), 7.10-7.83 (m, 4H,
aromatic).
General Procedure for Preparation of Alkylating
Agents 10a-c,e, 11a-e, and 12a-e. A cooled solution of
amine 9a-e (4.0 mmol) in CH2Cl2 was stirred vigorously with
2% aqueous NaOH (9.6 mL, 4.8 mmol) while the appropriate
ω-haloalkyl chloride (4.8 mmol) in CH2Cl2 was added dropwise.
The same NaOH solution was then used to maintain pH at 9,
and at constant pH the layers were separated. The organic
phase was washed with 3 N HCl and with H2O and then dried
over Na2SO4 and evaporated under reduced pressure. The
crude residue was chromatographed as detailed below to give
compounds 10a-c,e, 11a-e, and 12a-e as white semisolids.
N-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-4-chlo-
robutanamide (10a). Eluted with CHCl3/AcOEt, 1:1; 39%
yield. 1H NMR δ 1.72-1.86, 1.92-2.04 (m, 4H, endo-CH2CH2),
2.10-2.19 (m, 2H, CH2CH2CH2) 2.37 (t, 2H, J ) 7.2 Hz,
COCH2), 2.53-2.79 (m, 2H, benzylic CH2), 3.63 (t, 2H, J )
6.0 Hz, CH2Cl), 3.82 (s, 3H, CH3), 5.15-5.20 (m, 1H, CH), 5.75
(br d, 1H, NH), 6.72-7.18 (m, 3H, aromatic). GC-MS m/z 283
(M+ + 2, 1), 281 (M+, 2), 161 (26), 160 (100), 159 (27).
4-[4-(2-Methoxyphenyl)piperazin-1-yl)]butanoic acid
(14). Ester 13 (1.20 g, 3.9 mmol) was refluxed for 4 h in 20
mL of 4% aqueous NaOH. Then the mixture was cooled and
washed with CHCl3. The separated aqueous phase was neu-
tralized with 3 N HCl and extracted with AcOEt (3 × 30 mL).
The collected organic layers were dried over Na2SO4 and
evaporated under reduced pressure to give 0.58 g of acid 14
as a white solid (51% yield). 1H NMR δ 1.84-1.89 (m, 2H, CH2-
CH2CO), 2.58-2.62 (m, 2H, COCH2), 2.77 (br t, 2H, (CH2)2-
NCH2], 2.2.96 [br s, 4H, (CH2)2NCH2], 3.20 [br s, 4H, ArN-
(CH2)2], 3.87 (s, 3H, CH3), 6.87-7.06 (m, 3H, aromatic), 9.52
(br s, 1H, OH, D2O exchanged). GC-MS m/z 279 (M+ + 1, 20),
278 (M+, 96), 219 (25), 205 (100), 190 (39).
General Procedure for Preparation of Final Com-
pounds. A stirred mixture of alkylating agent 10a-c,e, 11a-
e, or 12a-e (8.0 mmol), 1-substituted piperazine (9.6 mmol),
and K2CO3 (8.0 mmol) in acetonitrile was refluxed overnight.
After cooling, the mixture was evaporated to dryness and H2O
(20 mL) was added to the residue. The aqueous phase was
extracted with AcOEt (2 × 30 mL). The collected organic layers
were dried over Na2SO4 and evaporated under reduced pres-
sure. The crude residue was chromatographed (CH2Cl2/CH3-
OH, 19:1, as eluent) to yield pure compounds 7, 15-22, 24-
43, and 45-50 as pale yellow oils. Yields were 20-30% for
butanamide derivatives, 35-44% for pentanamide derivatives,
and 65-75% for the other compounds.
4-(2-Methoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-
1
1-yl)-1-piperazinebutanamide (26). H NMR δ 1.75-1.93,
1.98-2.10 (m, 6H, COCH2CH2, endo-CH2CH2), 2.34 (t, 2H, J
) 7.0 Hz, COCH2CH2), 2.42-2.58 [m, 6H, CH2N(CH2)2], 2.76-
2.78 (m, 2H, benzylic CH2), 2.90 [br s, 4H, (CH2)2NAr], 3.84
(s, 3H, CH3), 5.19-5.29 (m, 1H, CH), 6.80-7.29 (m, 9H,
aromatic, NH). GC-MS m/z 408 (M+ + 1, 7), 407 (M+, 27), 392
(88), 245 (52), 205 (100).
4-(2-Methoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-
1-yl)-1-piperazinepentanamide (27). 1H NMR δ 1.56-1.85,
2.01-2.07 [m, 8H, CH2(CH2)2CH2, endo-CH2CH2], 2.25 (t, 2H,
J ) 7.3 Hz, COCH2CH2), 2.43 [t, 2H, J ) 7.3 Hz, CH2N(CH2)2],
2.62 [br s, 4H, CH2N(CH2)2], 2.71-2.79 (m, 2H, benzylic CH2),
3.06 [br s, 4H, (CH2)2NAr], 3.86 (s, 3H, CH3), 5.19-5.23 (m,
1H, CH), 5.79 (br d, 1H, NH), 6.84-7.25 (m, 8H, aromatic).
GC-MS m/z 422 (M+ + 1, 4), 421 (M+, 14), 406 (41), 259 (45),
205 (100), 131 (36).
N-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-5-chlo-
ropentanamide (11a). Eluted with CH2Cl2; 33% yield. 1H
NMR δ 1.75-1.85, 1.93-2.01 (m, 8H, CH2(CH2)2CH2, endo-
CH2CH2), 2.19-2.26 (m, 2H, COCH2), 2.55-2.73 (m, 2H,
benzylic CH2), 3.52-3.58 (m, 2H, CH2Cl), 3.81 (s, 3H, CH3),
5.14-5.19 (m, 1H, CH), 5.73 (br d, 1H, NH), 6.71-7.17 (m,
3H, aromatic). GC-MS m/z 297 (M+ + 2, 2), 295 (M+, 5), 161
(28), 160 (100), 159 (31), 145 (20).
N-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-6-bro-
mohexanamide (12a). Eluted with CH2Cl2; 35% yield. 1H
NMR: δ 1.43-1.53 [m, 2H, (CH2)2CH2(CH2)2], 1.61-1.99 [m,
8H, CH2CH2Br, COCH2CH2, endo-CH2CH2], 2.20 (t, 2H, J )
7.4 Hz, COCH2), 2.53-2.75 (m, 2H, benzylic CH2), 3.40 (t, 2H,
J ) 6.7 Hz, CH2Br), 3.81 (s, 3H, CH3), 5.17 (br t, 1H, CH),
5.69 (br d, 1H, NH), 6.74-7.17 (m, 3H, aromatic). GC-MS m/z
355 (M+ + 2, 1), 353 (M+, 1), 160 (100).
4-(2-Methoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-
1
1-yl)-1-piperazinehexanamide (28). H NMR δ 1.36-1.43
(m, 2H, CH2CH2CH2CH2CH2), 1.51-1.59, 1.61-1.86, 2.00-
2.06 (m, 8H, CH2CH2CH2CH2CH2, endo-CH2CH2), 2.21 (t, 2H,
J ) 7.6 Hz, COCH2), 2.40 [br t, 2H, CH2N(CH2)2], 2.64 [br s,
4H, CH2N(CH2)2], 2.71-2.80 (m, 2H, benzylic CH2), 3.09 [br
s, 4H, (CH2)2NAr], 3.86 (s, 3H, CH3), 5.17-5.23 (m, 1H, CH),
5.67 (br d, 1H, NH), 6.83-7.25 (m, 8H, aromatic). GC-MS m/z
436 (M+ + 1, 4), 435 (M+, 13), 420 (27), 273 (41), 205 (100).
4-(2-Acetylphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-
yl)-1-piperazinehexanamide (34). 1H NMR δ 1.33-1.43 (m,
2H, CH2CH2CH2CH2CH2), 1.51-1.86, 1.98-2.06 (m, 8H,
CH2CH2CH2CH2CH2, endo-CH2CH2), 2.21 (t, 2H, J ) 7.4 Hz,
COCH2), 2.43 [t, 2H, J ) 7.6 Hz, CH2N(CH2)2], 2.62 [br s, 4H,
CH2N(CH2)2], 2.65 (s, 3H, CH3), 2.71-2.79 (m, 2H, benzylic
CH2), 3.04 [br t, 4H, (CH2)2NAr], 5.17-5.29 (m, 1H, CH), 5.69
(br d, 1H, NH), 7.02-7.40 (m, 7H, aromatic). GC-MS m/z 448
(M+ + 1, 8), 447 (M+, 26), 299 (60), 287 (65), 273 (100), 217
(90).
Ethyl 4-[4-(2-Methoxyphenyl)piperazin-1-yl]butanoate
(13). A stirred mixture of 1-(2-methoxyphenyl)piperazine (1.50
g, 7.8 mmol), ethyl 4-bromobutanoate (0.9 mL, 6.3 mmol), and
K2CO3 (0.87 g, 6.3 mmol) in acetonitrile was refluxed over-
night. After the mixture was cooled, the mixture was evapo-
rated to dryness and H2O (20 mL) was added to the residue.
The aqueous phase was extracted with CH2Cl2 (2 × 30 mL).
The collected organic layers were dried over Na2SO4 and
evaporated under reduced pressure. The crude residue was
chromatographed (CHCl3/AcOEt, 1:1, as eluent) to afford pure
4-(2-Methylthiophenyl)-N-(1,2,3,4-tetrahydronaphtha-
1
len-1-yl)-1-piperazinehexanamide (44). H NMR δ 1.33-
1.43 (m, 2H, CH2CH2CH2CH2CH2), 1.53-1.63, 1.66-1.86,
2.00-2.06 (m, 8H, CH2CH2CH2CH2CH2, endo-CH2CH2), 2.22
(t, 2H, J ) 7.4 Hz, COCH2), 2.40 (s, 3H, CH3), 2.43 [t, 2H, J )
7.4 Hz, CH2N(CH2)2], 2.63 [br s, 4H, CH2N(CH2)2], 2.74-2.79
(m, 2H, benzylic CH2), 3.03 [br s, 4H, (CH2)2NAr], 5.18-5.29
(m, 1H, CH), 5.70 (br d, 1H, NH), 7.03-7.26 (m, 8H, aromatic).
GC-MS m/z 452 (M+ + 1, 2), 451 (M+, 8), 273 (61), 221 (100).
4-(2-Methylphenyl)-N-(1,2,3,4-tetrahydronaphthalen-
1
13 as a pale yellow oil (1.32 g, 68% yield). H NMR δ 1.24 (t,
3H, J ) 7.1 Hz, CH2CH3), 1.79-1.89 (m, 2H, CH2CH2CO), 2.34
(t, 2H, J ) 7.3 Hz, COCH2), 2.41 [t, 2H, J ) 7.4 Hz, (CH2)2-
NCH2], 2.63 [br s, 4H, (CH2)2NCH2], 3.06 [br s, 4H, ArN(CH2)2],
3.83 (s, 3H, OCH3), 4.11 (q, 2H, J ) 7.1 Hz, CH2CH3), 6.82-
7.00 (m, 3H, aromatic). GC-MS m/z 307 (M+ + 1, 18), 306 (M+,
77), 261 (32), 205 (100), 190 (37).
1
1-yl)-1-piperazinehexanamide (49). H NMR δ 1.34-1.44
(m, 2H, CH2CH2CH2CH2CH2), 1.53-1.63, 1.66-1.86, 2.00-