Synthesis of pyrido[2,3-d]pyridazines and pyrazino[2,3-d]-pyridazines-novel classes of GABAA receptor benzodiazepine binding site ligands

Article abstract of DOI:10.1016/j.tetlet.2006.01.084

Novel syntheses of 2,3,8-trisubstituted pyrido[2,3-d]pyridazines and 2,3,5-trisubstituted pyrazino[2,3-d]pyridazines are described. Two complementary routes to pyrido[2,3-d]pyridazines were developed, the first of which began by constructing the pyridine

Full text of DOI:10.1016/j.tetlet.2006.01.084

Tetrahedron Letters 47 (2006) 2257–2260
Synthesis of pyrido[2,3-d]pyridazines and
pyrazino[2,3-d]-pyridazines—novel classes of GABAA
receptor benzodiazepine binding site ligands
Andrew Mitchinson,* Wesley P. Blackaby, Sylvie Bourrain,
Robert W. Carling and Richard T. Lewis
Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow,
Essex CM20 2QR, UK
Received 9 November 2005; accepted 16 January 2006
Available online 3 February 2006
Abstract—Novel syntheses of 2,3,8-trisubstituted pyrido[2,3-d]pyridazines and 2,3,5-trisubstituted pyrazino[2,3-d]pyridazines are
described. Two complementary routes to pyrido[2,3-d]pyridazines were developed, the first of which began by constructing the pyr-
idine ring, and the second of which started by constructing the pyridazine ring. Pyrazino[2,3-d]pyridazines were prepared in a route
employing an aza-Wadsworth–Emmons cyclization as the key step. The resulting compounds were found to be high affinity ligands
for the GABAA receptor benzodiazepine binding site.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
As part of a program to find subtype selective agonists
for the benzodiazepine site of the GABAA receptor,
our laboratory has reported the discovery of triaz-
olo[4,3-c]pyridazines, such as 1 (see Fig. 1), which are
functionally selective GABAA a2/3 partial agonists.1,2
Compound 1 acts as a nonsedating anxiolytic in animal
models.3 We decided to investigate the structurally
related pyrido[2,3-d]pyridazine 2 and pyrazino[2,3-d]-
For the pyrido[2,3-d]pyridazine 2, our initial strategy
was to prepare the intermediate pyridone 8 (see Scheme
1), which it was envisaged could be cyclised with hydra-
zine hydrate to afford the fused ring system 10, and then
elaborated to the desired product 2. Starting from
aminoacetophenone hydrochloride 4,8 Boc protection
and then aldol reaction with dimethyl 2-ketoglutarate
afforded intermediate 5. The nitrogen was deprotected
with trifluoroacetic acid, and the resulting amine was
allowed to cyclise, yielding the lactam 6. Dehydration
of 6 was effected by heating at reflux in neat trifluoro-
acetic acid, and oxidation of the resulting product with
DDQ furnished the pyridone 7. However, numerous
attempts to reduce the ester group of 7 with a variety
of reducing agents failed to afford the desired ketoalde-
hyde 8. It was therefore decided to cyclise with hydra-
zine hydrate at the ketoester stage, and manipulate the
oxidation state of the resulting ring system later. The
pyridone was selectively O-benzylated using silver
carbonate as base in toluene,9 and the resulting product
was reacted with hydrazine hydrate to afford the
fused ring system 9. This was deoxygenated by a
chlorination/catalytic transfer hydrogenation proce-
dure to afford the desired intermediate 10. Classical
pyridazines
3 as potential new GABAA ligands.
Although these fused ring systems are reasonably well
represented in the literature,4,5 very little precedent
existed for the specific substitution patterns that we
required (i.e., 2,3,8-substitution for
2 and 2,3,5-
substitution for 3). In this letter, we report new synthetic
routes to these synthetically challenging tri-substituted
heterocycles.6,7
Keywords: Pyridopyridazines; Pyrazinopyridazines; Aza-Wadsworth–
Emmons cyclization; GABAA receptor ligands.
*
Corresponding author. Tel.: +44 01279 440266; fax: +44 01279
440390; e-mail: andrew_mitchinson@merck.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.084

2258
A. Mitchinson et al. / Tetrahedron Letters 47 (2006) 2257–2260
F
N
N
N
N
N
N
N
N
N
N
N
N
Ph
R1
O
N
O
N
O
Me
R2
Et
N
N
N
N
N
N
1
2
3
Figure 1. Functionally selective GABAA a2/3 partial agonist 1 and related structures.
i) BOC2O, NEt3, CH2Cl2
MeO2C
O
ii) LDA, THF, -78 oC
O
HCl.H2N
MeO2C
Ph
NHBOC
O
Ph
HO
4
5
iii) MeO2C
CO2Me , -78 oC to rt
59%
i) TFA
ii) NEt3, CH2Cl2
61%
MeO2C
O
MeO2C
O
MeO2C
HO
O
H
DDQ, toluene
reflux, 38%
TFA, reflux
100%
Ph
Ph
Ph
NH
NH
NH
7
O
O
O
6
i) AgCO3, BnBr, toluene
ii) NH2NH2.H2O, EtOH, reflux
steps
X
66%
H
N
N
O
O
O
N
i) POCl3, reflux
N
ii) NH4HCO2, Pd/C,
Ph
Ph
Ph
propan-2-ol, reflux
96%
NH
NH
N
9
10
O
8
O
OBn
Br2, AcOH,
90 oC
41%
N
N
N
Me
N
N
N
N
Ph
N
PhSnBu3
Cl
N
N
5 mol% Pd2dba3,
N
Ph
Ph
Ph
20 mol% AsPh3,
O
N
Cs2CO3, DMF
44%
NH
NH
DMF, 80 oC
63%
Ph
Br
2
11
O
12
O
Me
N
Scheme 1. Preparation of tri-substituted pyrido[2,3-d]pyridazine 2.
hydrogenation with hydrogen gas led to partial reduc-
tion of the pyrido[2,3-d]pyridazine ring system. The
transfer hydrogenation had to be performed in sterically
hindered propan-2-ol as the solvent, as the intermediate
chloride was rapidly displaced with other alcohols. Bro-
mination of 10 was surprisingly sluggish, requiring sev-
eral days of heating in order to achieve a modest yield
of 11. Once in place, the bromide could be coupled in
a Stille reaction, installing the desired phenyl group,
and then the pyridone 12 could be alkylated with our re-
quired side chain,10 affording the target compound 2.11
A complementary strategy for the pyrido[2,3-d]pyrida-
zines is shown in Scheme 2. In this approach the

A. Mitchinson et al. / Tetrahedron Letters 47 (2006) 2257–2260
2259
O
F
O
O
F
O
F
O
ONO
NMe2
Cl
Me
HCl (g), Et2O, 5 oC
toluene
21% over 2 steps
N
N
O
HO
13
14
15
NH2NH2.H2O,
EtOH
N
N
N
N
F
N
F
N
F
MnO2,
H2, Pd/C (cat)
THF-CH2Cl2
67%
EtOAc,
9% over 2 steps
O
NH2
18
OH
NH2
17
N
O
16
Cl
NEt3, DMF
45%
O
N
N
N
F
N
F
HO
TsOH
toluene, 80 oC,
75%
NH
NH
O
O
19
20
Scheme 2. Alternative route to tri-substituted pyrido[2,3-d]pyridazines.
pyridazine ring was made first, and then the fused ring
system was constructed. 20-Fluoroacetophenone 13
was converted to its analogous hydroximoyl chloride
14 by the method of Brachwitz.12 Compound 14 was
unstable to purification, so it was used crude in a cycli-
sation reaction with 3-dimethylaminoacrolein, affording
the isoxazole 15 in modest yield over the two steps.
Compound 15 was cyclised with hydrazine, but once
again the resulting intermediate 16 was unstable, so this
was subjected to hydrogenation as a crude product,
furnishing the pyridazine 17 in low yield over two steps.
Oxidation of the alcohol in 17 was achieved by the
action of manganese(IV) oxide, and the resulting amino
aldehyde 18 was cyclised with phenylacetyl chloride to
give the bicyclic system 19. This was dehydrated with
p-toluenesulfonic acid affording the pyrido[2,3-d]pyrida-
zin-2-one 20, analogous to 12 in Scheme 1.
The desired isomer 26b was isolated by recrystallisation.
DCC coupling of 26b with keto-acids occurred with
concomitant aza-Wadsworth–Emmons cyclisation,14
directly affording the fused ring system 27. Finally, alkyl-
ation of 27 with the required side chains,1 this time using
a Mitsunobu protocol, gave the target compounds 3.15
Pyrido[2,3-d]pyridazine 2 is a high affinity antagonist for
the GABAA BZ binding site (Ki = 0.45 nM for the a1
subtype; 0.31 nM for the a3 subtype).16 The analogous
pyrazino[2,3-d]pyridazine 3a (R1 = Ph, R2 = Et) has
much lower affinity (Ki: a1 = 9.2 nM, a3 = 15 nM) com-
pared to 2, but this can be recovered by replacing the R1
phenyl group with t-Bu, affording 3b (Ki: a1 = 0.14 nM,
a3 = 0.24 nM).
3. Conclusion
The pyrazino[2,3-d]pyridazines 3 were prepared as
shown in Scheme 3. Acetophenone 21 was converted
by a modified literature procedure,13 in one pot, into
the pyridazinone 22. This was brominated at the 5-posi-
tion with N-bromosuccinimide, affording the highly
insoluble product 23. This was exhaustively protected
with Boc-anhydride to give the soluble intermediate
24. The pyridazinone oxygen was selectively deprotected
and the bromide was displaced with azide, affording the
intermediate 25. The azide 25 could be obtained directly
from 24 under the azide displacement conditions, but in
lower yield than the two-step procedure. The azide was
reduced via hydrogenation, the remaining protecting
groups were cleaved, and the carbonyl was removed
via a chlorination/hydrogenation procedure, affording
a 1:2 mixture of the phosphoramidates 26a and 26b.
New routes have been developed to prepare 2,3,4-trisub-
stituted pyrido[2,3-d]pyridazines (such as 2) and 2,3,5-
trisubstituted pyrazino[2,3-d]pyridazines 3, structures for
which no precedent existed in the literature prior to this
work. Two complementary methods were employed to
prepare pyrido[2,3-d]pyridazines, differing in which ring
of the fused system was prepared first, that is, the pyri-
dine or the pyridazine. The route to the pyrazino[2,3-d]-
pyridazines 3 involved an aza-Wadsworth–Emmons
cyclisation as a key step, representing a completely new
approach to the synthesis of such heterocycles. The
resulting compounds were high affinity ligands for
the GABAA BZ binding site, and so represent new struc-
tural classes of these important biologically active
molecules.

2260
A. Mitchinson et al. / Tetrahedron Letters 47 (2006) 2257–2260
O
H
N
H
O
O
O
N
O
i)
, 100 oC
NBS, MeCN,
reflux, 86%
N
HO
N
ii) NH4OH
Me
Ph
H2N
Ph
23
H2N
Ph
21
iii) NH2NH2.H2O, reflux
59%
Br
22
BOC2O,
DMAP, DMF,
64%
NH.HN3
H
N
H
BOCO
N
O
O
N
N
Me2N
NMe2
K2CO3,
N
N
DMF, 70 oC
MeOH, 95%
(BOC)2N
Ph
(BOC)2N
Ph
(BOC)2N
Ph
Br
88%
N3
Br
24
25
H2, Pd/C,
EtOH,
CH2Cl2
72%
N
i) HCl, MeOH
ii) POCl3, PhNMe2,
reflux
H
N
N
N
N
P
O
O
P
N
H2N
Ph
+
EtO
N
Ph
(BOC)2N
Ph
EtO
H
HN
O
iii) H2, Pd/C, EtOH
79%
NH2
NH2
EtO
26b
26a
OEt
R1COCO2H,
DCC, THF-CH2Cl2
54 - 98%
N
N
N
R2
N
N
N
N
R1 = alkyl, Ph, 2-furyl, 2-thienyl,
4-morpholinyl
N
Ph
HO
N
R1
N
Ph
NH
O
N
R2 = Me, Et
R1
PPh3, DEAD,
CH2Cl2, 31 - 58%
3
O
27
R2
N
N
Scheme 3. Preparation of pyrazino[2,3-d]pyridazines.
7. Blackaby, W. P.; Lewis, R. T.; Street, L. J. Patent
Application WO 2001/051492.
References and notes
8. Meyer, H.-J.; Wolff, T. Chem. Eur. J. 2000, 6, 2809.
9. Chung, N. M.; Tieckelmann, H. J. Org. Chem. 1970, 35,
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1. Russell, M. G. N.; Carling, R. W.; Atack, J. R.; Bromidge,
F. A.; Cook, S. M.; Hunt, P.; Isted, C.; Lucas, M.;
McKernan, R. M.; Mitchinson, A.; Moore, K. W.;
Narquizian, R.; Macaulay, A. J.; Thomas, D.; Thompson,
S.-A.; Wafford, K. A.; Castro, J. L. J. Med. Chem. 2005,
48, 1367.
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N.; Moore, K. W.; Mitchinson, A.; Sohal, B.; Pike, A.;
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10. Carling, W. R.; Mitchinson, A.; Moore, K. W.; Russell,
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2000/023449.
1
11. Data for compound 2: MS: (ES+) m/e 395 (M+H)+; H
NMR (400 MHz, CDCl3): d 3.62 (3H, s), 5.67 (2H, s), 7.48
(3H, m), 7.56 (3H, m), 7.63 (2H, m), 7.85 (1H s), 8.13 (2H,
m), 8.20 (1H, s), 9.49 (1H, s).
12. Brachwitz, H. Z. Chem. 1966, 6, 313.
13. Coates, W. J.; McKillop, A. Heterocycles 1989, 29,
1077.
14. Moody, C. J.; Rees, C. W.; Thomas, R. Tetrahedron 1992,
17, 3589.
15. Data for a typical compound, 3a: MS: (ES+) m/e 410
(M+H)+; 1H NMR (400 MHz, DMSO-d6): d 9.79 (1H, s),
8.18 (2H, m), 8.13 (2H, m), 7.97 (1H, s), 7.58 (6H, m), 5.78
(2H, s), 4.13 (2H, q, J 7.2 Hz), 1.19 (3H, t, J 7.2 Hz).
16. Measured at receptors stably expressed in L(tkꢀ) cells by
displacement of [3H]Ro15-1788 binding, means for n = 3–5.
4. Sako, M. Sci. Synth. 2004, 16, 1109.
5. Ishikawaw, T. Sci. Synth. 2004, 16, 1337.
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