Design, synthesis, and evaluation of fused heterocyclic analogs of SCH 58261 as adenosine A2A receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2008.05.069

SCH 58261 is a reported adenosine A_2A receptor antagonist which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A₁ receptor and does not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinetics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A_2A receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A_2A receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model of Parkinson's Disease, and has aqueous solubility of 100 μM at physiological pH.

Full text of DOI:10.1016/j.bmcl.2008.05.069

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4204–4209
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, and evaluation of fused heterocyclic analogs of SCH 58261
as adenosine A2A receptor antagonists
*
Unmesh Shah, Claire M. Lankin, Craig D. Boyle , Samuel Chackalamannil, William J. Greenlee,
Bernard R. Neustadt, Mary E. Cohen-Williams, Guy A. Higgins, Kwokei Ng, Geoffrey B. Varty,
Hongtao Zhang, Jean E. Lachowicz
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
SCH 58261 is a reported adenosine A2A receptor antagonist which is active in rat in vivo models of Par-
kinson’s Disease upon ip administration. However, it has poor selectivity versus the A1 receptor and does
not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinet-
ics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and
synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A2A
receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine
4s has excellent A2A receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model
Received 12 March 2008
Revised 15 May 2008
Accepted 16 May 2008
Available online 22 May 2008
Keywords:
Adenosine
A2A
A2A receptor
A2A antagonist
A2A receptor antagonist
SCH 58261
of Parkinson’s Disease, and has aqueous solubility of 100
l
M at physiological pH.
Ó 2008 Elsevier Ltd. All rights reserved.
Parkinson’s Disease
As described in the preceding publication,1 adenosine A2A
receptor antagonism is a potential treatment for Parkinson’s Dis-
ease.2,3 SCH 58261 (Fig. 1, 1) has previously been identified as a
high-affinity A2A receptor antagonist.4 However, SCH 58261 is only
moderately selective for A2A receptors over A1 receptors,5 has poor
solubility,6 and does not produce in vivo activity when dosed oral-
ly.4c Attempts via phenyl substitution to produce soluble analogs
which maintain the biological activity of SCH 58261 were unsuc-
cessful.6 We have previously demonstrated that quinoline analogs
of SCH 58261 can improve A2A selectivity as well as pharmacoki-
netics and oral efficacy.1 In addition, replacement of the phenyl
group of SCH 58261 with a piperazine moiety can produce potent
and selective A2A receptor antagonists.7 While these modifications
have improved upon the in vitro and in vivo properties of SCH
58261, the reported lead compounds all have poor aqueous solu-
bility.7 To follow up on these discoveries, our plan was to attach
fused heterocyclic moieties (2) with the SCH 58261 tricyclic core
3 (Scheme 1). Our rationale was that incorporation of the more ba-
sic nitrogen present in fused heterocyclic side-chains (2) could re-
sult in water soluble A2A receptor antagonists (4) which also
improve the potency and selectivity of SCH 58261. Described here-
NH2
N
1
SCH 58261 ( )
N
N
O
N
A2A Ki = 2 nM
N
A1/A2A = 53
N
Figure 1. SCH 58261.
in are the syntheses and structure–activity relationships of novel
fused heterocyclic analogs which demonstrate aqueous solubility
and improve upon the pharmacological and pharmacokinetic pro-
files of SCH 58261.
The general synthesis of the fused heterocyclic analogs of SCH
58261 is depicted in Scheme 1.8 Displacement of the tosylate 37a
with the corresponding free amine 2 furnished the desired targets
4 reported throughout this publication. The first heterocyclic ana-
logs we explored were isoindolines, which were synthesized as
shown in Scheme 2.9 Generally, the isoindoline analogs met the
in vitro criteria with A2A binding affinity in the range of 5–15 nM
and an acceptable selectivity profile (Table 1).10 Compound 4d
demonstrated improved selectivity and solubility over SCH
58261 and was studied further. Unfortunately, this compound
showed low plasma levels in a rat pharmacokinetic assay11 and
was only moderately active in a haloperidol-induced catalepsy as-
say in rat.12
* Corresponding author. Tel.: +1 908 740 3503; fax: +1 908 740 7152.
E-mail address: craig.boyle@spcorp.com (C.D. Boyle).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.069

U. Shah et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4204–4209
4205
NH2
NH2
N
n
n
N
N
O
N
O
N
N
N
DMF
100 oC
R
NH
n
2a-y
TsO
R
N
n
N
X
N
N
X
N
N
3
4a-y
X = CH, N
n = 1, 2
X = CH, N
n = 1, 2
Scheme 1. General synthesis of fused heterocyclic SCH 58261 analogs.
O
O
O
a, b
c , d, e
NH
N Bn
OR'
O
O
OR
OH
2b: R' = Me
6 R = Ac
5
7
R = H
2c:
R' = MeOCH2CH2-
g, e
f
Br
Br
NH
MeO
MeO
MeO
8
9
2d
Scheme 2. Synthesis of isoindolines. Reagents and conditions: (a) BnNH2, THF, reflux. (b) Ac2O, reflux. (c) LAH, THF, reflux. (d) R0X, NaH, DMF. (e) Pd(OH)2/C, HCO2NH4, MeOH,
reflux. (f) NBS, benzoyl peroxide, CCl4, reflux. (g) BnNH2, toluene, reflux.
Table 1
Structure–activity relationship of isoindoline analogs
NH2
N
N
O
N
N
X
N
N
a
Compound
X
A2A Ki (nM)
A1/A2A
116
k. sol.b
37
(
lM)
Rat AUCc
287
Catalepsyd
3 mpk po, 1 h/4 h
e
4a
14.7
—
N
N
4b
4c
6.0
7.1
5.4
105
105
126
—
—
—
OMe
N
75
37
215
199
—
O
MeO
MeO
4d
N
21/24
a
For a detailed description of the human adenosine receptor binding assays see Ref. 10.
A single measurement of kinetic solubility at pH 7.4.13
b
c
Area under the curve: h.ng/mL, 0 ? 6h, 3 mpk, 20% HPbCD, po.11
Inhibition of haloperidol-induced catalepsy is an in vivo measure of A2A antagonist activity (>30% inhibition is considered to be active in this assay).12
Not determined.
d
e
Tetrahydroisoquinoline analogs were explored next. Commer-
Mono-substitution at the 6- and 7-positions of the tetrahydro-
isoquinoline moiety resulted in compounds 4i and 4j, which
showed acceptable A2A potency, but suffered from modest selectiv-
ity over A1. Nevertheless, these compounds were studied further
and were shown to possess acceptable rat plasma levels. When
tested in vivo, both compounds demonstrated promising anticata-
leptic activity at 3 mpk. Compound 4j was also moderately active
at 1 mpk in the catalepsy assay. Having seen a good selectivity pro-
cial tetrahydroisoquinolines and custom synthesized alkoxy inter-
mediates (Scheme 3) displaced the tosylate 3 to yield the final
targets 4e–4k.14 Both 3- and 1-substituted tetrahydroisoquinoline
derivatives 4f and 4g met the binding criteria and demonstrated
good solubility (Table 2). However, these compounds failed to
show activity in the catalepsy assay, which was attributed to their
poor pharmacokinetic properties.

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U. Shah et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4204–4209
syntheses of intermediates 2r, 2s, 2w, and 2x have been reported
a, b
c, d
O
in the literature.16,19 The remaining tetrahydronaphthyridine
intermediates were derived via cyclization of the dinitropyridone
1317 to the 3-nitrotetrahydroisoquinoline intermediates 14 and
15.18 Intermediates 14 and 15 were reduced to their free amines
which underwent Sandmeyer chemistry to form the bromide 2u
and alcohol 16. Compounds 2u and 16 were further elaborated to
produce 2y, 2t, and 2v.
MeO
HO
NH
NH
NBn
MeO
2h:
2k: 7-isomer
8-isomer
10
11
Scheme 3. Synthesis of tetrahydroisoquinolines.14 Reagents and conditions: (a)
BnBr, Et3N, EtOH. (b) BBr3, CH2Cl2, 0 °C ? rt. (c) NaH, MeOCH2CH2Br, DMF.
(d) Pd(OH)2/C, HCO2NH2, MeOH, reflux.
A comparison of compounds in Table 4 shows that the use of
tetrahydronaphthyridine resulted in potent analogs that generally
exhibited good rat pharmacokinetics and aqueous solubility. Com-
pounds 4r, 4s, and 4u all had excellent AUC values, and were active
in vivo. However, of all of the tetrahydronaphthyridine com-
pounds, only the methyl analog 4s improved upon the selectivity
profile of SCH 58261. It also possessed excellent solubility
file for the extended ether 4h, we synthesized compound 4k.
Unfortunately, it did not improve the selectivity profile and was
not studied further.
Analogs based on the benzazepine moiety, synthesized as
shown in Scheme 4,15 were also explored. Several compounds of
this class showed promising binding affinity and improved selec-
tivity (Table 3) compared to the isoindoline and tetrahydroisoquin-
oline analogs. Unfortunately, these compounds failed to exhibit
acceptable plasma levels and suffered from poor in vivo activity
in the catalepsy assay.
(100
l
M), rat AUC (3491 ng ꢀ h/mL, 3 mpk, po), and displayed po-
tent oral anti-cataleptic activity at doses of 3 mpk (80% inhibition
@ 1 h) and 1 mpk (65% inhibition @ 1 h). The compound also
showed anticataleptic activity at the 4 h time point (ꢁ35% inhibi-
tion @ 1 mpk).
Having seen promising anticataleptic activity for the tetrahy-
droisoquinoline analogs, we decided to synthesize the correspond-
ing tetrahydronaphthyridine counterparts (Scheme 5).16–19 The
Compound 4s was studied further and a complete rat pharma-
cokinetic profile was generated at 3 mpk. It possessed good oral
Table 2
Structure–activity relationship of tetrahydroisoquinoline analogs
NH2
N
N
N
O
N
X
N
N
a
Compound
X
A2A Ki (nM)
A1/A2A
k. sol.b
50
(
lM)
Rat AUCc
60
Catalepsyd
3 mpk po, 1 h/4 h
4e
4.1
94
35/0
0/26
N
MeO
MeO
4f
1.9
2.3
149
37
12
0
0
N
N
MeO
MeO
4g
146
313
28/20
Ph
O
N
4h
1.5
37
31
0/0
MeO
MeO
4i
4j
2.5
3.2
68
60
25
37
688
357
65/35
N
N
50/58
26/61 (1 mpk)
MeO
MeO
e
4k
5.1
56
50
—
—
N
O
a
For a detailed description of the human adenosine receptor binding assays see Ref. 10.
A single measurement of kinetic solubility at pH 7.4.13
b
c
Area under the curve: h.ng/mL, 0 ? 6h, 3 mpk, 20% HPbCD.11
d
e
Inhibition of haloperidol-induced catalepsy is an in vivo measure of A2A antagonist activity (>30% inhibition is considered to be active in this assay).12
Not determined.

U. Shah et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4204–4209
4207
NH
X
a, b or
a, c
2n
2o
(X = Br)
(X = Cl)
NH
O2N
g, h
2m
N Bn
NH
d, e, f
HO
RO
2p:
R = Me
12
2q: R = MeOCH2CH2-
Scheme 4. Synthesis of benzazepines.15 Reagents and conditions: (a) 10% Pd/C, H2, MeOH. (b) i—48% HBr, NaNO2/H2O, 0 °C; ii—CuBr, HBr, H2O. (c) i—20% HCl, NaNO2/H2O,
0 °C; ii—CuCl, HCl/H2O. (d) BnBr, Et3N, EtOH. (e) NiCl2ꢀ6H2O, NaBH4, MeOH, 0 ° C ? rt. (f) i—5% aq. H2SO4, NaNO2/H2O, 0 °C; ii—5% aq. H2SO4, 100 °C. (g) RBr, NaH, DMF,
0 °C ? rt. (h) Pd(OH)2/C, HCO2NH4, MeOH, reflux.
Table 3
Structure–activity relationship of benzazepine analogs
NH2
N
N
O
N
N
X
N
N
a
Compound
X
A2A Ki (nM)
A1/A2A
k. sol.b
(
lM)
Rat AUCc
48
Catalepsyd
3 mpk po, 1 h/4 h
4l
2.0
215
71
0
0/17
—
N
e
4m
4n
N
0.7
1.1
< 5
6
—
O2N
Br
62
—
—
N
4o
4p
3.3
1.9
2.0
33
—
—
—
N
Cl
N
463
306
< 2.5
< 2.5
0
5/8
0/0
MeO
MeO
N
4q
103
O
a
For a detailed description of the human adenosine receptor binding assays see Ref. 10.
A single measurement of kinetic solubility at pH 7.4.13
b
c
Area under the curve: h.ng/mL, 0 ? 6 h, 3 mpk, 20% HPbCD, po.11
d
e
Inhibition of haloperidol-induced catalepsy is an in vivo measure of A2A antagonist activity (>30% inhibition is considered to be active in this assay).12
Not determined.
O2N
Boc
Br
X
N
NH
NH
h, i, k or
h, j, k
b-e
f, g
O
O
NBoc
NBn
, a
, a
N
N
N
O2N
NO2
O
14
2u
2y
2t
(X = Ph)
(X =
c
-Pr)
N
CH3
13
RO
O2N
Bn
HO
Bn
NH
N
N
l, m
N
N
N
2v
15
16
(R = MeOCH2CH2-)
Scheme 5. Synthesis of tetrahydronaphthyridines.17 Reagents and conditions: (a) 7 N NH3 in MeOH, reflux.18 (b) TFA, CH2Cl2. (c) H2, 10% Pd/C, MeOH. (d) NaNO2, HBr, 0 °C. (e)
CuBr, HBr, 100 °C. (f) SnCl2ꢀ2H2O, concd HCl, EtOH, 50 °C.18 (g) i—5% aq. H2SO4, NaNO2/H2O, 0 °C; ii—5% aq. H2SO4, 100 °C. (h) Ph3CCl, Et3N, DMAP, CH2Cl2. (i) PhB(OH)2,
Pd(PPh3)4, Na2CO3, toluene, 100 °C. (j) i—Tributyl(vinyl)tin, Pd(PPh3)4, DMF, 100 °C; ii—CH2N2,Et2O. (k) 3 N HCl, acetone. (l) MeOCH2CH2Br, NaH, DMF, 0 °C ? rt. (m) Pd(OH)2/
C, HCO2NH4, MeOH, reflux.

4208
U. Shah et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4204–4209
Table 4
Structure–activity relationship of tetrahydronaphthyridine analogs
NH2
N
N
N
O
N
X
N
N
a
Compound #
X
A2A Ki (nM)
A1/A2A
k. sol.b
>250
(l
M)
Rat AUCc
1792
Catalepsyd
3 mpk po, 1 h/4 h
N
4r
4.8
64
50/30
15/0 (1 mpk)
N
N
4s
2.0
179
100
3491
85/30
60/35 (1 mpk)
N
N
4t
1.9
1.6
3.1
53
61
82
75
214
0/0
N
Br
N
4u
4v
37
2018
477
65/30
N
O
N
e
175
—
MeO
N
N
N
N
4w
4x
6.2
5.0
23
20
>250
37
467
—
—
N
1237
F3C
Ph
N
N
4y
17.9
27
—
—
—
N
a
For a detailed description of the human adenosine receptor binding assays see Ref. 10.
A single measurement of kinetic solubility at pH 7.4.13
b
c
Area under the curve: h.ng/mL, 0 ? 6 h, 3 mg/kg, 20% HPbCD, po.11
d
e
Inhibition of haloperidol-induced catalepsy is an in vivo measure of A2A antagonist activity (>30% inhibition is considered to be active in this assay).12
Not determined.
AUC (7980 ng ꢀ h/mL), a long half-life (t1/2 = 11.3 h), and low plas-
ma clearance (4.7 mL/min/kg). Compound 4s also exhibited excel-
lent oral bioavailability (F = 71%).
McNemar, William Windsor, and Mr. Ashwin Ranchod for provid-
ing solubility data. We also thank Drs. Pradip Das and Ben Prama-
nik for obtaining analytical data.
In conclusion, we have discovered novel heterocyclic analogs of
SCH 58261 as promising adenosine A2A receptor antagonists. Sev-
eral compounds displayed single digit A2A binding affinity and
were highly selective over the A1 receptor. Additionally, by incor-
porating polar heterocyclic moieties, we achieved improved aque-
ous solubility. The highly soluble tetrahydronaphthyridine analog
4s demonstrated potent oral anticataleptic activity and a promis-
ing pharmacokinetic profile in rats. Further characterization of
the compound 4s and related analogs is currently in progress.
References and notes
1. Shah, U.; Boyle, C. D.; Chackalamannil, S.; Neustadt, B. R.; Lindo, N.; Greenlee,
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The authors thank Professors Ronald Breslow and Scott Rych-
novsky, Drs. Michael Graziano, John Hunter, John Piwinski, Andrew
Stamford, and Catherine Strader for helpful discussions. We also
thank Drs. Mark Liang, Jesse Wong, and Mr. Y. Jin for providing
the tricyclic intermediate 3. In addition, we thank Drs. Charles

U. Shah et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4204–4209
4209
E.; Cash, W. D.; Psychoyos, S.; Ghai, G.; Wenk, P.; Friedmann, R. C.; Atkins, C.;
Warren, V.; Furness, P.; Hyun, J. L.; Stone, G. A.; Desai, M.; Williams, M. J. Med.
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Seymour, P. A.; Koe, B. K. J. Med. Chem. 1990, 33, 2240.
Fawzi, A.; Cohen-Williams, M. E.; Varty, G. B.; Tulshian, D. B. Bioorg. Med. Chem.
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13. The nephelometric (light scattering) method was used to determine the kinetic
solubility of compounds. The test compound (1.0 mg) was dissolved in DMSO
6. Baraldi, P. G.; Cacciari, B.; Romagnoli, R.; Spalluto, G.; Monopoli, A.; Ongini, E.;
Varani, K.; Borea, P. A. J. Med. Chem. 2002, 45, 115.
at 25 mM.A serial dilution into DMSO was performed and 3 ll of the compound
in DMSO at various concentrations was added to the buffer (10 mM phosphate,
pH 7.4). Presence of precipitate was detected by nephelometry. Solubility was
defined as the highest concentration of material that did not scatter light
Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev.
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7. (a) Neustadt, B. R.; Hao, J.; Lindo, N.; Greenlee, W. J.; Stamford, A. W.; Tulshian,
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Silverman, L. S.; Caldwell, J. P.; Greenlee, W. J.; Kiselgof, E.; Matasi, J. J.;
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8. All compounds in this publication were isolated and tested in free base form.
9. Intermediate 2a is commercially available from Aldrich Chemical Company,
Inc., Milwaukee, WI.
10. Binding Assay: Matasi, J. J.; Caldwell, J. P.; Hao, J.; Neustadt, B.; Arik, L.; Foster,
C.; Lachowicz, J.; Tulshian, D. Bioorg. Med. Chem. Lett. 2005, 15, 1333. footnote
11. Functional assays run on selected compounds throughout the A2A program
indicate that similar pyrazolotriazolopyrimidines are antagonists with Kb
values approximating the binding assay derived Ki values. In addition, affinity
for the rat A1 and A2A receptors did not differ from affinity for the human
receptor.
14. Tetrahydroisoquinolines 2i, 2j, and 10 were synthesized as described in: Sall, D.
J.; Grunewald, G. L. J. Med. Chem. 1987, 30, 2208. Intermediates 2e–2g are
commercially available from Acros Organics, Morris Plains, NJ.
15. Benzazepine 2m was synthesized as described in: Pecherer, B.; Sunbury, R. C.;
Brossi, A. J. Heterocycl. Chem. 1971, 8, 779. The unsubstituted intermediate 2l is
commercially available from Scientific Exchange, Inc., Center Ossipee, NH.
16. The synthesis of intermediate 2r is reported in the following reference:
Shiozawa, A.; Ichikawa, Y.-I.; Ishikawa, M.; Kogo, Y.; Kurashige, S.; Miyazaki,
H.; Yamanaka, H.; Sakamoto, T. Chem. Pharm. Bull. 1984, 32, 995; The synthesis
of intermediate 2s is reported in the following reference: Shiozawa, A.;
Ichikawa, Y.-I.; Komuro, C.; Kurashige, S.; Miyazaki, H.; Yamanaka, H.;
Sakamoto, T. Chem. Pharm. Bull. 1984, 32, 2522.
11. Procedure described in: Cox, K. A.; Dunn-Meynell, K.; Korfmacher, W. A.;
Broske, L.; Nomeir, A. A.; Lin, C.-C.; Cayen, M. N.; Barr, W. H. Drug Discovery
Today 1999, 4, 232. %CV values typically range from 10 to 30 in this assay
(n = 2).
12. (a) Inhibition of haloperidol-induced catalepsy is an in vivo assay used to
evaluate Parkinson’s drugs (>30% inhibition is considered to be active in this
assay); (b) Mandhane, S. N.; Chopde, C. T.; Ghosh, A. Eur. J. Pharmacol. 1997,
328, 135; Procedure described in: (c) Matasi, J. J.; Caldwell, J. P.; Zhang, H.;
17. Intermediate 13 was synthesized as described in: Matsumura, E.; Ariga, M.;
Tohda, Y. Bull. Chem. Soc. Jpn. 1979, 39, 2413.
18. Cyclization of 13 to form a 3-nitrotetrahydronaphthyridine is reported in:
Harling, J. D.; Harrington, F. P.; Thompson, M. Synth. Commun. 2001, 31, 787.
19. The synthesis of intermediate 2w is reported in: Fukui, H.; Inoguchi, K.;
Nakano, J. Heterocycles 2002, 56, 257; The synthesis of intermediate 2x is
described in: Ashton, W. T.; Caldwell, C. G.; Duffy, J. L.; Mathvink, R. J.; Wang,
L.; Weber, A. E. WO Patent 2004069162, 2004.