Antagonists of the human adenosine A2A receptor. Part 3: Design and synthesis of pyrazolo[3,4-d]pyrimidines, pyrrolo[2,3-d]pyrimidines and 6-arylpurines

Article abstract of DOI:10.1016/j.bmcl.2008.03.072

A series of pyrazolo[3,4-d]pyrimidine, pyrrolo[2,3-d]pyrimidine and 6-arylpurine adenosine A_2A antagonists is described. Many examples were highly selective against the human A₁ receptor sub-type and were active in an in vivo model of Parkinson's disease.

Full text of DOI:10.1016/j.bmcl.2008.03.072

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 2924–2929
Antagonists of the human adenosine A2A receptor. Part 3:
Design and synthesis of pyrazolo[3,4-d]pyrimidines,
pyrrolo[2,3-d]pyrimidines and 6-arylpurines
Roger J. Gillespie,a Ian A. Cliffe,a Claire E. Dawson,a Colin T. Dourish,a
Suneel Gaur,a Allan M. Jordan,b Antony R. Knight,a Joanne Lerpiniere,a
Anil Misra,a Robert M. Pratt,a Jonathan Roffey,a Gemma C. Stratton,a
Rebecca Upton,a Scott M. Weissa and Douglas S. Williamsonb,*
aVernalis (R&D) Ltd, 613 Reading Road, Winnersh RG41 5UA, UK
bVernalis (R&D) Ltd, Granta Park, Cambridge CB21 6GB, UK
Received 10 January 2008; revised 26 March 2008; accepted 27 March 2008
Available online 30 March 2008
Abstract—A series of pyrazolo[3,4-d]pyrimidine, pyrrolo[2,3-d]pyrimidine and 6-arylpurine adenosine A2A antagonists is described.
Many examples were highly selective against the human A1 receptor sub-type and were active in an in vivo model of Parkinson’s
disease.
Ó 2008 Elsevier Ltd. All rights reserved.
Adenosine A2A receptors play a role within the brain in
regulating movement, and there is strong evidence that
they may provide a novel therapy for the treatment of
Parkinson’s disease.1,2 Further to the discovery that 4-
arylthieno[3,2-d]pyrimidines such as compound 1 were
potent adenosine A2A receptor antagonists, selective
over the A1 receptor and demonstrated activity in a
mouse haloperidol-induced hypolocomotion model of
Parkinson’s disease,3–7 the SAR around other bicyclic
heteroaromatic templates was explored.
The 4-(furan-2-yl)pyrazolo[3,4-d]pyrimidine 2 was se-
lected as a starting point for further investigation and,
encouragingly, this was found to have an A2A Ki of
48 nM and was 13-fold selective over A1 (Table 1).8 1-
Benzyl substitution (compound 3) increased potency at
A2A and selectivity over A1, whilst retaining in vivo
activity. Saturation of the phenyl ring of 3 or incorpora-
tion of heteroatoms (compounds 4–6) was tolerated, but
did not improve affinity significantly. Extension of the
linker between the phenyl ring and pyrazole by one
methylene group (compound 7) was detrimental to
A2A potency, but further extension (compounds 8 and
9) regained A2A potency at the expense of A1 selectivity.
Elaboration of the 2-amino substituent was also ex-
plored, but its replacement with a 2-aminoethanol or
2-dimethylamino substituent (10 and 11) reduced A2A
potency.
O
S
N
N
NH2
1
A2A Ki 14 nM
A1 Ki 479 nM
Given the encouraging data on the benzyl analogue 3,
the effects of substitution around the phenyl ring were
explored (Table 2). Meta-substitution with a range of
electron-rich and deficient substituents was tolerated,
with the 3-chlorobenzyl analogue 14 showing increased
A2A potency and selectivity over A1. Ortho- and para-
substitution was largely detrimental to the desired bio-
logical profile, although 2-fluoro substitution (com-
pound 23) was tolerated. Further work was
Keywords: Adenosine A2A receptor antagonists; Parkinson’s disease;
Pyrazolo[3,4-d]pyrimidine; Pyrrolo[2,3-d]pyrimidine; Purine.
*
Corresponding author. Tel.: +44 (0) 1223 895555; fax: +44 (0) 1223
895556; e-mail: d.williamson@vernalis.com
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.03.072

R. J. Gillespie et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2924–2929
Table 1. Binding affinity and in vivo activity of pyrazolo[3,4-d]pyrimidines 2–11
2925
O
N
N
R2
N
N
R1
Compound
R1
R2
A2A Ki (nM)8
A1 Ki (nM)8
HaloLMA activity4–6
2
3
H
Benzyl
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
48
3
647
468
763
1953
709
462
17
Active
Active
Active
Active
Active
Inactive
Active
Active
Inactive
—
4
Cyclohexylmethyl
Pyridin-3-ylmethyl
Furan-2-ylmethyl
Phenethyl
45
28
5
6
36
7
110
4
8
3-Phenylpropyl
Benzylaminocarbonyl
Phenethyl
9
1
13
10
11
NH(CH2)2OH
NMe2
135
1891
175
7255
Phenethyl
Table 2. Binding affinity and in vivo activity of pyrazolo[3,4-d]pyrimidines 2–3 and 12–33, and 9-substituted-6-(furan-2-yl)-9H-purin-2-ylamines 34–
47
R2
X
N
Y
N
N
NH2
R1
Compound
X
Y
R1
R2
A2A Ki (nM)6
A1 Ki (nM)6
HaloLMA activity4
2
3
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
N
H
Benzyl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Thiophen-2-yl
Pyridin-2-yl
Pyrazol-3-yl
Thiazol-2-yl
48
3
647
468
Active
Active
Active
Inactive
Active
Active
Active
Inactive
Active
Inactive
Active
Active
Inactive
Active
Active
Inactive
Inactive
—
N
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
N
3-Methylbenzyl
2-Chlorobenzyl
3-Chlorobenzyl
3-Methoxybenzyl
3-Methoxycarbonylbenzyl
2-Nitrobenzyl
3
252
721
N
9
N
1
206
284
N
2
N
4
779
N
26
4
1605
497
N
3-Nitrobenzyl
4-Nitrobenzyl
N
119
8
1610
320
N
2-Aminobenzyl
3-Aminobenzyl
3-Carboxybenzyl
2-Fluorobenzyl
2,6-Difluorobenzyl
4-Trifluoromethylbenzyl
4-Methylsulfonylbenzyl
2-Fluorobenzyl
2-Fluorobenzyl
2-Fluorobenzyl
2-Fluorobenzyl
2-Fluorobenzyl
2-Fluorobenzyl
2-Fluorobenzyl
H
N
4
123
N
1322
4
6321
264
N
N
2
130
47
N
6
N
340
9
1126
193
N
N
12
16
17
71
1616
2086
261
40
6
519
Active
Active
Inactive
Active
Inactive
—
N
1642
504
N
N
(1,2,4)Triazol-3-yl
1-Methylimidazol-2-yl
Imidazol-2-yl
Furan-2-yl
1993
6219
4900
4951
3324
1083
984
N
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
Active
Active
Active
Inactive
Active
Inactive
Inactive
—
N
Benzyl
Furan-2-yl
Furan-2-yl
N
3-Methylbenzyl
3-Chlorobenzyl
3-Methoxybenzyl
3-Methoxycarbonylbenzyl
3-Nitrobenzyl
N
Furan-2-yl
Furan-2-yl
8
N
7
1680
1938
3920
5765
4027
6470
1444
612
N
Furan-2-yl
Furan-2-yl
45
85
372
23
4105
5
N
N
4-Nitrobenzyl
Furan-2-yl
Furan-2-yl
N
3-Aminobenzyl
3-Carboxybenzyl
2-Fluorobenzyl
2,6-Difluorobenzyl
4-Trifluoromethylbenzyl
4-Methylsulfonylbenzyl
Active
—
N
Furan-2-yl
Furan-2-yl
N
Active
Active
Active
—
N
Furan-2-yl
Furan-2-yl
Furan-2-yl
3
N
6
779
3288
7628
N

2926
R. J. Gillespie et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2924–2929
undertaken to optimise the 4-(furan-2-yl) substituent of
23 since, in some compounds, this moiety is prone to
oxidative metabolism, which can lead to the formation
of reactive species capable of forming covalent adducts.9
This iterative approach is complementary to database
mining and molecular similarity approaches, which have
been used to identify other classes of non-furan contain-
ing A2A antagonists.10 The resulting compounds 27–33
showed reduced affinity for A2A, although the pyrazol-
3-yl analogue 29 displayed increased A1 selectivity,
whilst retaining in vivo activity.
et al.,11 published subsequent to our patent disclosure.12
Appropriate substitution on the phenyl ring led to in-
creased potency, with some examples displaying affinity
for A2A at a similar level to their pyrazolo[3,4-d]pyrim-
idine counterparts, as well as greater selectivity over
A1. The 2,6-difluorophenyl analogue 45 was the most
potent example in this sub-series (A2A Ki 3 nM, A1 Ki
612 nM). Whilst several analogues were active in vivo
following ip administration, the 3-aminobenzyl
analogue 42 was the only example which showed
in vivo efficacy, when dosed orally at 30 mg/kg.
Despite many pyrazolo[3,4-d]pyrimidine examples
showing in vivo activity following intraperitoneal
administration, none were active when given orally.
Modification of the core template of this series to a pur-
ine was investigated, with a view to obtaining orally ac-
tive compounds. The 6-arylpurine 34 had weaker
binding affinity for A2A (Ki 261 nM) than compound
2, but had similar selectivity over A1 (Ki 4951 nM).
Additionally, 34 caused reversal of haloperidol-induced
hypolocomotion in mice dosed at 10 mg/kg ip and,
encouragingly, at 1 mg/kg po.
With the intention of further optimising the in vivo pro-
file of the 6-arylpurine series, it was noted that the urea
analogue 9 of the pyrazolo[3,4-d]pyrimidine series had
an A2A Ki of 1 nM and was 13-fold selective over A1.
The analogous 6-arylpurine compound 48 was synthes-
ised, and was found to have a very similar level of po-
tency for A2A and selectivity over A1 (Table 3). The
phenyl analogue 49 had a similar in vitro profile to the
unsubstituted compound 34, but the introduction of
an extra two methylene spacers (50) led to improved
selectivity over A1 and incorporation of an (S)-a-meth-
ylbenzyl substituent (51) enhanced A2A potency whilst
maintaining >100-fold selectivity over A1. A range of
heteroaryl and substituted phenyl analogues (53–58)
was shown to be highly potent at A2A, selective for A1
and active in vivo when dosed ip. Additionally, com-
pounds 53, 54 and 56 were shown to be orally active
in vivo at 30, 10 and 30 mg/kg, respectively.
As with the pyrazolo[3,4-d]pyrimidine examples, ben-
zylic substitution (compound 35) at the 9-position of
compound 34 was beneficial to affinity for the A2A
receptor and also selectivity over A1. This compound
was also active in vivo when dosed at 30 mg/kg ip, but
inactive when administered orally at the same dose. In
comparison with the analogous pyrazolo[3,4-d]pyrimi-
dine 3, however, compound 35 was 13-fold less potent
against A2A. Further studies were carried out to opti-
mize compound 35. These augment the work of Kiselgof
SAR at the 6-position of the purine ring was investi-
gated, with the furan-2-yl ring of compound 48 being re-
placed with thiophen-2-yl, phenyl or thiazol-5-yl groups
Table 3. Binding affinity and in vivo activity of pyrazolo[3,4-d]pyrimidine 9 and 6-aryl-9H-purin-9-ylcarboxamides 48–65
R2
X
N
Y
N
N
R3
H
N
O
R1
Compound
X
Y
R1
R2
R3
A2A Ki (nM)8
A1 Ki (nM)8
HaloLMA activity4–6
9
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
CH
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Benzyl
Benzyl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
OMe
SMe
NMe2
Me
1
1
13
17
Active
Active
Active
Active
Active
Inactive
Active
Active
Active
Active
Active
Active
Inactive
Active
Active
—
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
Phenyl
Phenethyl
206
6
4960
624
231
1856
28
(S)-1-Phenylethyl
(R)-1-Phenylethyl
Thiophen-2-ylmethyl
Furan-2-ylmethyl
4-Fluorobenzyl
3-Methylbenzyl
4-Methylbenzyl
2-Chlorobenzyl
Benzyl
2
26
1
2
170
70
1
1
26
76
1
1
26
Thiophen-2-yl
Phenyl
13
17
56
8
127
60
Benzyl
Benzyl
Thiazol-5-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
Furan-2-yl
835
534
547
748
2726
Benzyl
Benzyl
13
23
102
Inactive
Inactive
—
Benzyl
Benzyl

R. J. Gillespie et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2924–2929
2927
(59–61). In all cases, potency at A2A and selectivity over
O
N
A1 was reduced. Replacement of the 2-amino group of
compound 48 with OMe, SMe, NMe2 or Me (62–65)
was detrimental to A2A potency, but gave enhanced
selectivity over A1.
N
N
N
NH2
R
(iv)
(v)
O
N
Cl
N
3-8 and 12-26
(i)-(iii)
Selected pyrrolo[2,3-d]pyrimidine analogues were also
prepared, allowing comparison with the direct
analogues in the pyrazolo[3,4-d]pyrimidine series
(Table 4). Examples 66 and 67 showed that replacement
of N-2 with CH resulted in a significant drop in potency
at A2A, along with a smaller drop in selectivity over A1.
N
N
N
N
H
O
N
NH2
N
H
N
NH2
68
2
N
N
N
NH2
Ph
N
H
O
9
Pyrazolo[3,4-d]pyrmidines were prepared using the fol-
lowing methodology.13 4-Chloro-1H-pyrazolo[3,4-
d]pyrimidin-6-ylamine 6814 underwent Boc-protection
and then arylation with 2-(tributylstannyl)furan in the
presence of bis(triphenylphospine)palladium(II) dichlo-
ride, followed by deprotection to afford compound 2
(Scheme 1). Subsequent treatment with sodium hydride,
followed by a benzyl or alkyl bromide, afforded com-
pounds 3–8, 12–19 and 23–26 as largely the desired
N1-substituted regioisomer.15 Reduction of the
nitrobenzyl analogs 17 and 18 with tin(II) chloride affor-
ded the aminobenzyl analogs 20 and 21, respectively,
and hydrolysis of the methyl ester 16 afforded the
carboxylic acid 22. The benzyl urea 9 was synthesized
by treatment of 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrim-
Scheme 1. Reagents and conditions: (i) Boc2O, Et3N, DMAP, DMF,
rt, 23%; (ii) 2-(tributylstannyl)furan, PdCl2(PPh3)2, DMF, rt, 99%; (iii)
Me2NH(aq) (40% w/v), D, 70%; (iv) NaH, DMF, 0 °C; RCH2Br, rt, 34–
100%; (for 20 and 21) SnCl2Æ2H2O, concd HCl, EtOH, 50–70 °C, 94%;
(for 22) 1 M NaOH(aq), MeOH, D, 95%; (v) PhCH2NCO, DMAP,
DMF, rt, 24%.
Cl
CN
NH2
N
N
(i) - (iii)
N
N
N
R1
N
Cl
R1
69
70
R1 = Ph(CH2)2
(iv)
idin-6-ylamine
dimethylaminopyridine.
2 with benzyl isocyanate and 4-
O
N
O
N
(v)
An alternative synthetic strategy (Scheme 2) involved
hydrolysis of 5-amino-1-phenethyl-1H-pyrazole-4-car-
bonitrile 6916 with sulfuric acid, followed by cyclocon-
densation of the resulting acid with urea and treatment
with phenylphosphonic dichloride, which afforded 4,6-
dichloro-1-phenethyl-1H-pyrazolo[3,4-d]pyrimidine 70.
Subsequent arylation with 2-(tributylstannyl)furan in
the presence of bis(triphenylphospine)palladium(II)
dichloride afforded compound 71. The 6-Cl of 71 under-
went displacement by primary and secondary amines to
afford 10 and 11.
N
N
R2
N
N
N
Cl
N
N
R1
R1
R3
71
10 R2 = H, R3 = (CH2)2OH
11 R2 = R3 = Me
Scheme 2. Reagents and conditions: (i) 9 M H2SO4(aq), 60 °C, 47%; (ii)
CO(NH2)2, 180 °C, quant.; (iii) PhPOCl2, 165 °C, 23%; (iv) 2-(tribu-
tylstannyl)furan, PdCl2(PPh3)2, DMF, rt, 99%; (v) (for 10)
HO(CH2)2NH2, NMP, 100 °C, 57%; (for 11) Me2NH(aq) (40% w/v),
i-PrOH, D, 67%.
Scheme 3 outlines the synthesis of compounds 27–33. 4-
Chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine 68 was
treated with sodium hydride, followed by 1-bromo-
Cl
N
Ar
N
N
N
N
N
Cl
N
N
N
NH2
NH2
(ii) or
(iii) or
(iv)
R
R
N
72
27-33
+
N
(i)
Table 4. Comparison of in vitro binding activity and in vivo activity of
pyrazolo[3,4-d]pyrmidines 2 and 23, and pyrrolo[2,3-d]pyrimidines 66
and 67
N
H
NH2
+
Cl
68
Ar
N
N
R
N
O
R
N
R = 2-F-PhCH2
N
N
N
NH2
N
NH2
N
73
74
X
N
N
NH2
Scheme 3. Reagents and conditions: (i) NaH, DMF, 0 °C; 1-bromo-
methyl-2-fluorobenzene, 0 °C to rt, 34%; (ii) (for 27), ArB(OH)2,
Pd(PPh3)4, satd NaHCO3(aq), THF, D, 20%; (iii) (for 28) 2-bromopyr-
idine, n-BuLi, THF, À78 °C; 1 M ZnCl2 in Et2O, À78 °C to rt; 72 and
73 (as 1:1 mixture), Pd(PPh3)4, D, 19%; (iv) (for 30 and 32) ArH, n-
BuLi, THF, À78 °C; 1 M ZnCl2 in Et2O, À78 °C to rt; 72 and 73 (1:1
mixture), Pd(PPh3)4, D, 19–21%; (iv) (for 29, 31 and 33) N-SEM-ArH,
n-BuLi, THF, À78 °C; 1 M ZnCl2 in Et2O, À78 °C to rt; 72 and 73 (1:1
mixture), Pd(PPh3)4, D, 2 h, 31%; 4 M HCl in 1,4-dioxane, rt, 23–40%.
R
Compound
R
X
N
A2A Ki A1 Ki HaloLMA
(nM)8 (nM)8 activity4–6
2
H
H
48
647
2765
264
Active
Active
Active
—
66
23
67
CH 242
2-Fluorobenzyl
2-Fluorobenzyl CH
N
4
16
709

2928
R. J. Gillespie et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2924–2929
methyl-2-fluorobenzene, to give a 1:1 mixture of N1 and
N2 benzylated derivatives 72 and 73. This mixture then
underwent a range of Suzuki couplings with an aryl
boronic acid or Negishi couplings with an aryl zinc re-
agent. The desired N1-benzylated regiosomers 27–33
were then isolated from the undesired N2-benzylated
regioisomers of type 74.15
nyl)furan to give intermediates 78 or 79 (Scheme 6). 2-
Chloro displacement, followed by deprotection and sub-
sequent treatment with benzyl isocyanate afforded 62–
65.
4-(Furan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamines
66 and 67 were prepared as follows (Scheme 7).18 2,4-Di-
chloro-7H-pyrrolo[2,3-d]pyrimidine 8019 underwent
Boc-protection and then 4-arylation with 2-(tributyl-
stannyl)furan to give compound 81. Displacement of
the 2-chloro substituent of 81 with veratrylamine, fol-
lowed by treatment with trifluoracetic acid, gave com-
pound 66. Compound 67 could be prepared by
benzylation of 80, followed by arylation to give interme-
diate 82 and then subsequent amine displacement and
treatment with trifluoracetic acid.
6-Aryl purines were prepared as follows.12 2,6-Dichloro-
purine 7517 underwent Boc-protection followed by 6-
arylation with 2-(tributylstannyl)furan (Scheme 4). Dis-
placement of the 2-Cl with veratrylamine followed by
TFA deprotection afforded compound 34. Alkylation
of 34 with a benzyl bromide afforded compounds 35–
41 and 44–47. Reduction of the 3-nitrobenzyl analogue
40 with tin(II) chloride afforded the aniline 42, and basic
hydrolysis of the methyl ester 39 afforded the carboxylic
acid 43. Treatment of compound 34 with the appropri-
ate isocyanate afforded ureas 48–58.
In conclusion, a series of pyrazolo[3,4-d]pyrimidine, pyr-
rolo[2,3-d]pyrimidine and 6-arylpurine adenosine A2A
antagonists was described. Many examples were highly
THP-protection of 2-amino-6-chloropurine 76, followed
by Suzuki or Stille arylation and then deprotection,
afforded compounds of type 77, which underwent treat-
ment with benzyl isocyanate to afford ureas 59–61
(Scheme 5).
O
(iii), (iv), (v)
,
N
N
N
63
2,6-Dichloropurine 75 underwent Boc- or SEM-protec-
tion and subsequent arylation with 2-(tributylstan-
N
Cl
boc
Cl
N
(i), (ii)
78
N
N
N
H
(vi), (ii)
O
Cl
O
62,
75
(vii) or (viii) or (ix)
then (x), (v)
N
N
64
N
N
N
and
65
O
Cl
N
(v)
N
Cl
N
N
NH2
SEM
(i)-(iv)
N
Ar
N
79
N
N
35-47
N
H
Cl
N
H
Scheme 6. Reagents and conditions: (i) Boc2O, Et3N, DMAP, THF,
rt, quant.; (ii) 2-(tributylstannyl)furan, PdCl2(PPh3)2, DMF, 96%; (iii)
NaSMe, NMP, 110 °C, 61%; (iv) 4 M HCl in 1,4-dioxane, 1,4-dioxane,
rt, 87%; (v) PhCH2NCO, DMAP, THF, DMF, 35–82%; (vi) SEMCl,
NaH, THF 0 °C to rt, 78%; (vii) (for 62) MeONa, MeOH, D, 67%;
(viii) (for 64) NHMe2, i-PrOH, D, 86%; (ix) (for 65) Me3Al, Pd(PPh3)4,
Cl(CH2)2Cl, D, 30%; (x) 1 M TBAF in THF, THF, D, 43–76%.
N
NH2
(vi)
75
34
O
N
N
N
N
NH2
H
N
O
R
48-58
Scheme 4. Reagents and conditions: (i) Boc2O, Et3N, DMAP, THF,
rt, quant.; (ii) 2-(tributylstannyl)furan, PdCl2(PPh3)2, DMF, 96%; (iii)
veratrylamine, NMP, 120 °C, 50%; (iv) CF3CO2H, 60 °C, 57%; (v)
NaH, DMF, 0 °C; ArCH2Br, 20–88%; (for 42 only) SnCl2Æ2H2O,
concd HCl, EtOH, 50 °C, 22%; (for 43 only) 1 M NaOH(aq), MeOH, D,
95%; (vi) RNCO, DMAP, DMF, 65 °C, 28–97%.
O
N
O
N
(iii), (iv)
N
boc
(i), (ii)
N
H
N
Cl
N
NH2
Cl
N
81
66
N
H
N
Cl
Ar
O
(v), (ii)
O
N
80
Cl
N
Ar
N
N
N
N
(i), (ii) or (iii)
then (iv)
(iii), (iv)
N
N
N
(v)
N
N
N
NH2
H
N
N
N
N
H
N
H
N
NH2
N
Cl
NH2
NH2
O
Ph
76
77
59-61
82
67
F
F
Scheme 5. Reagents and conditions: (i) 3,4-dihydro-2H-pyran, 1 M
HCl in Et2O, DMF, 60 °C, 78%; (ii) (for 59 and 60) ArB(OH)2,
Pd(PPh3)4, satd NaHCO3(aq), THF, D, 51–72%; (iii) (for 61) ArSnBu3,
Pd(PPh3)2Cl2, DMF, 80 °C, 75%; (iv) Amberlyst, MeOH, D; NH3,
MeOH, rt, 72–89%; (v) PhCH2NCO, DMAP, DMF, 70 °C, 76–87%.
Scheme 7. Reagents and conditions: (i) Boc2O, Et3N, DMAP, THF,
rt, 52%; (ii) 2-(tributylstannyl)furan, PdCl2(PPh3)2, DMF, rt, 61%; (iii)
veratrylamine, NMP, 100 °C, 88%; (iv) CF3CO2H, 50 °C, 51%; (v)
NaH, DMF, 0 °C; 1-bromomethyl-2-fluorobenzene, rt, 76%.

R. J. Gillespie et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2924–2929
2929
Table 5. Comparison of binding affinity and in vivo activity (following
ip and po dosing) of selected 6-arylpurines
5. Bezard, E.; Imbert, C.; Gross, C. E. Rev. Neurosci. 1998, 9,
71.
6. Mandhane, S. N.; Chopde, C. T.; Ghosh, A. K. Eur. J.
Pharmacol. 1997, 328, 135.
7. Weiss, S. M.; Benwell, K.; Cliffe, I. A.; Gillespie, R. J.;
Knight, A. R.; Lerpiniere, J.; Misra, A.; Pratt, R. M.;
Revell, D.; Upton, R.; Dourish, C. T. Neurology 2003, 61,
S101.
8. Ki values are the means of at least three determinations.
9. Broughton, H. B.; Watson, I. A. J. Mol. Graphics Modell.
2004, 23, 51.
Compound
A2A Ki
(nM)8
A1 Ki
(nM)8
HaloLMA activity4–6
MED
(mg/kg) ip
MED
(mg/kg) po
34
42
53
54
56
261
23
1
4951
4027
28
10
10
1
30
30
10
30
ꢀ30
<30
1
2
170
26
1
10. Richardson, C. M.; Gillespie, R. J.; Williamson, D. S.;
Jordan, A. M.; Fink, A.; Knight, A. R.; Sellwood, D. M.;
Misra, A. Bioorg. Med. Chem. Lett. 2006, 16, 5993.
11. Kiselgof, E.; Tulshian, D. B.; Arik, L.; Zhang, H.; Fawzi,
A. Bioorg. Med. Chem. Lett. 2005, 15, 2119.
12. Gillespie, R. J.; Lerpiniere, J.; Dawson, C. E.; Gaur, S.;
Pratt, R. M.; Stratton, G. C.; Weiss, S. M. PCT Int. Appl.
WO 2002055521, 2002.
selective against the human A1 receptor sub-type and
showed efficacy in a mouse haloperidol-induced hypolo-
comotion model of Parkinson’s disease, following ip
administration. 6-Arylpurines 42, 53, 54 and 56 showed
efficacy in this model following oral administration, but
each had an MED greater than that for the parent pur-
ine 34 (Table 5). In comparison with 34, the urea and
benzyl derivatives are more lipophilic and, although
rat PK studies showed good brain penetration, they
had low oral bioavailability. Studies also showed that
the urea side-chains were vulnerable to cleavage
in vivo, and so these compounds were not progressed
further. Subsequent work in this area will be disclosed
in due course.
13. Gillespie, R. J.; Lerpiniere, J.; Gaur, S. PCT Int. Appl.
WO 2002055082, 2002.
14. Seela, F.; Steker, H. Heterocycles 1985, 23, 2521.
1
15. In H NMR spectroscopic studies of compounds 3–8 and
12–33, there was no nuclear Overhauser enhancement
(nOe) of the signals pertaining to the protons of the benzyl
substituent, following irradiation of the pyrazole 3-H. For
compounds of type 74, which were isolable during the
synthesis of compounds 27–33, nOe of the signal pertain-
ing to the protons of the benzylic methylene group was
observed upon irradiation of the pyrazole 3-H, thus
confirming N2 benzyl substitution in compounds of type
74 and, indirectly, confirming that benzylation had
occurred at N1 of 3–8 and 12–33. Comparison of 1H
and 13C NMR data for compounds 3–8 and 12–33 and
that for compounds 10 and 11, which were prepared from
the unambiguously N1-substituted pyrazole 69, further
supported the structural assignment.
References and notes
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Moro, S.; Spalluto, G.; Volpini, R. ChemMedChem 2007,
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3. Gillespie, R. J.; Cliffe, I. A.; Dawson, C. E.; Dourish, C.
T.; Gaur, S.; Giles, P. R.; Jordan, A. M.; Knight, A. R.;
Lawrence, A.; Lerpiniere, J.; Misra, A.; Pratt, R. M.;
Todd, R. S.; Upton, R.; Weiss, S. M.; Williamson, D. S.
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4. Reversal of haloperidol-induced hypolocomotion in mice,
dosed with 30 mg/kg ip of test compound unless otherwise
stated.
16. Baraldi, P. G.; Cacciari, B.; Spalluto, G.; Pineda de las
Infantas y Villatoro, M. J.; Zocchi, C.; Dionisotti, S.;
Ongini, E. J. Med. Chem. 1996, 39, 1164.
17. Obtained from the Sigma Aldrich Company Ltd, Gilling-
ham, Dorset, UK; http://www.sigmaaldrich.com.
18. Gillespie, R. J.; Lerpiniere, J. PCT Int. Appl. WO
2002055084, 2002.
19. Kazimierczuk, Z.; Cottam, H. B.; Revankar, G. R.;
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