5546
B. G. Sundar et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5543–5546
O
N
N
(a)
(b)
N
N
(c)
HO2C
OMe
O
OH
OMe
(f)
O
(d) (e)
O
N
N
O
O
Me
N
N
N
R
O
(g)
(h)
N
R = alkyl
R = boc
R = H
Scheme 1. Preparation of ethers 1–3. Reagents and conditions: (a) MeNHNH2, i-PrOH, reflux, 15 h, 95%; (b) MnO2, xylene, reflux, 14 h, 75%; (c) BBr3, CH2Cl2, 5 °C to rt, 5 h,
98%; (d) Cl(CH2)3Br, K2CO3, CH3CN, reflux, 20 h, 91%; (e)
-methylpyrrolidineÁHCl, K2CO3, NaI, CH3CN, 90 °C, 15 h, 48%; (f) N-boc-4-hydroxypiperidine, DEAD, Ph3P, THF, 0 °C
to rt; (g) TFA, CH2Cl2, rt, 3 h; (h) ketone, NaCNBH3, AcOH, MeOH, DMF, 60 °C.
a
HO
O
O
N
O
N
O
N
N
(c)
(a)
(b)
Br
N
Br
N
n
R
Scheme 2. Preparation of amines 4–7. Reagents and conditions: (a) MeNHNH2, i-PrOH, reflux, 15 h; (b) SeO2, AcOH, 100 °C, 16 h, 72%, 2 steps; (c) amine, Pd2dba3, BINAP,
NaOBut, toluene, 80 °C, 40–70%.
R
R
O
O
(a)
(b)
N
N
O
(c)
(d)
N
N
N
O
N
O
O
OH
OH
R
11 Me
12 4-F-Ph
13
H
Scheme 3. Preparation of amides 11–13. Reagents and conditions: (a) glyoxylic acid, AcOH, 110 °C, 20 h; (b) RNHNH2, 100 °C, 5 h; (c) SOCl2, 70 °C, 1 h; (d) amine, Et3N,
CH2Cl2, 0 °C to rt, 72%.
Pharmacol. 2007, 73, 1084; (b) Beavers, L. S.; Finley, D. R.; Gadski, R. A.;
Hipskind, P. A.; Hornback, W. J.; Jesudasan, C. D.; Pickard, R. T.; Takawuwa,
WO07005503, 2007.; (c) Hipskind, P. A.; Takawuwa, C. D.; Jesudasan, R. A.;
Gadski, R. A.; Hornback, W. J.; Pickard, R. T.; Neavers, L. S. WO06107661, 2006.
Compound 11 may have advantages for peripheral indications of
H3R antagonists, such as allergic rhinitis, with good PK and lower
brain levels.14 Additional profiling and SAR around the pyridazi-
6. Cowart, M.; Altenbach, R.; Black, L.; Faghih, R.; Zhao, C.; Hancock, A. A. Mini-
none cores will be disclosed in future reports.
Rev. Med. Chem. 2004, 4, 979.
7. Hudkins, R. L.; Raddatz, R.; Tao, M.; Mathiasen, J. R.; Aimone, L. D.; Becknell, N.
References and notes
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