3558 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 16
Brief Articles
Hz, CH3), 2.80 (m, 4H, H-pip), 2.95 (m, 2H, CH2), 3.45-3.50
(m, 4H, H-pip), 4.10 (quart 2H, CH2-CH3), 4.25 (t, 2H, J ) 6
Hz, CH2), 6.80-6.95 (m, 4H, H-arom), 7.68 (s, 1H, H6-pyrid),
11.82 (s, 1H, NH-pyrid).
1H NMR (CDCl3) δ: 2.60-2.79 (m, 6H, 4H-pip, CH2), 3.54-
3.59 (m, 4H, H-pip), 3.96-4.05 (m, 1H, CH-benzodioxan-),
4.28-4.42 (m, 2H, CH2-benzodioxan-), 6.75-6.90 (m, 4H,
H-arom), 7.60 (s, 1H, H6-pyrid), 11.29 (s, 1H, NH-pyrid).
Meth od B Exa m p le. 2-(7-Br om oh ep tyl)-4-ch lor o-5-{4-
[2-(2-e t h oxyp h e n oxy)e t h yl]p ip e r a zin -1-yl}p yr id a zin -
3(2H)-on e (21d ). A mixture of 20d (7.60 g, 20 mmol), 1,7-
dibromoheptane (7.75 g, 30 mmol), and dry potassium carbonate
(4.15 g, 30 mmol) in 70 mL of acetone was refluxed under
stirring for 22 h. The mixture was evaporated under reduced
pressure and purified by chromatography on a silica gel
column, eluting with a EtOH/CH2Cl2 mixture (3:97) to give
30% yield of dense oil. 1H NMR (CDCl3) δ: 1.25-1.45 (m, 9H,
3CH2, CH3), 1.76-1.85 (m, 4H, 2CH2), 2.75-2.80 (m, 4H,
H-pip), 2.89-2.93 (m, 2H, CH2), 3.35-3.45 (m, 6H, CH2, 4H-
pip), 4.00-4.20 (m, 6H, 3CH2), 6.88-6.95 (m, 4H, H-arom),
7.59 (s, 1H, H6-pyrid).
Meth od C Exa m p le. 2-{7-[4-(2-Meth oxyp h en yl)p ip er -
a zin -1-yl]h ep tyl}-4-ch lor o-5-{4-[2-(1,4-ben zod ioxa n yl)m -
eth yl]p ip er a zin -1-yl}p yr id a zin -3(2H)-on e (7). This com-
pound was obtained from 21b and 1-(2-methoxyphenyl)-
piperazine 22a following the same synthetic procedure applied
for 2. The mixture was refluxed under stirring for 6 h, and
the compound was purified by chromatography on a silica gel
column, eluting with a EtOH/CH2Cl2 mixture (5:95) to give a
50% yield of a dense oil. 1H NMR (CDCl3) δ: 1.25-1.47 (m,
6H, 3CH2), 1.76-1.79 (m, 2H, CH2), 2.30-2.42 (m, 2H, CH2),
2.58-2.78 (m, 10H, 8H-pip, CH2), 3.09-3.15 (m, 4H, H-pip),
3.37-3.41 (m, 4H, H-pip), 3.84 (s, 3H, OCH3), 3.95-4.11 (m,
5H, CH2-benzodioxan-, CH-benzodioxan-, CH2), 4.15-4.33 (m,
2H, CH2-benzodioxan-,), 6.80-6.90 (m, 8H, H-arom), 7.58 (s,
1H, H6-pyrid). For the corresponding hydrochloride: mp 62-
68 °C. Anal. (C35H47ClN6O4‚3HCl) C, H, N.
The corresponding 5-substituted isomer 20b was eluted with
EtOH/CH2Cl2 (5:95) to give 35% yield of a solid product.
Ack n ow led gm en t. Financial support provided by
the Italian MIUR (“Progettazione e Sintesi di Agenti
Neuroprotettivi”) is gratefully acknowledged. M.B. thanks
the Merck Research Laboratories for the 2002 Academic
Development Program Chemistry Award.
Su p p or tin g In for m a tion Ava ila ble: Details of the syn-
thesis and spectral data of some representative compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Refer en ces
(1) A portion of our research in this field was previously reported
in the following. Betti, L.; Floridi, M.; Giannaccini, G.; Manetti,
F.; Strappaghetti, G.; Tafi, A.; Botta, M. Bioorg. Med. Chem. Lett.
2003, 13, 171-173.
(2) Barbaro, R.; Betti, L.; Botta, M.; Corelli, F.; Giannaccini, G.;
Maccari, L.; Manetti, F.; Strappaghetti, G.; Corsano, S. Synthe-
sis, Biological Evaluation, and Pharmacophore Generation of
New Pyridazinone Derivatives with Affinity toward R1- and R2-
Adrenoreceptors. J . Med. Chem. 2001, 44, 2118-2132.
(3) Betti, L.; Botta, M.; Corelli, F.; Floridi, M.; Giannaccini, G.;
Maccari, L.; Manetti, F.; Strappaghetti, G.; Tafi, A.; Corsano,
S. R1-Adrenoceptor Antagonists. 4. Pharmacophore-Based De-
sign, Synthesis and Biological Evaluation of New Imidazo-,
Benzimidazo-, and Indolo-arylpiperazine Derivatives. J . Med.
Chem. 2002, 45, 3603-3611.
(4) Betti, L.; Botta, M.; Floridi, M.; Giannaccini, G.; Manetti, F.;
Strappaghetti, G. Pyridazinone Derivatives as R1-Adrenoceptor
Antagonists. Synthesis and their Application in the Field of
Health. Italian Patent RM2002A000362, J uly 5, 2002.
(5) Cheng, Y.-C.; Prusoff, W. H. Relationship between the Inhibition
Constant (Ki) and the Concentration of Inhibitor Which Causes
50 Per Cent Inhibition (IC50) of an Enzymatic Reaction. Biochem.
Pharmacol. 1973, 22, 3099-3108.
Meth od D Exa m p le. 4-{4-[(1,4-Ben zod ioxa n yl)-2-m e-
th yl]p ip er a zin -1-yl}-5-ch lor op yr id a zin -3(2H)-on e (23b).
A mixture of 1-[2-(1,4-benzodioxan)methyl]piperazine 19b
(0.989 g, 4.23 mmol), 18 (0.70 g, 4.23 mmol), and dry KHCO3
(0.42 g, 4 mmol) in 50 mL of dry 1,4-dioxane was refluxed
under stirring for 24 h. The mixture was filtered, and the
filtrate was evaporaed under reduced pressure. In particular,
the 4-substituted isomer 23b was eluted with EtOH/ CH2Cl2
(3:97) to give 62% yield of a solid product: mp 136-139 °C.
J M0307842