Design and synthesis of novel 2,3-dihydro-1H-isoindoles with high affinity and selectivity for the dopamine D3 receptor

Article abstract of DOI:10.1016/S0960-894X(01)00037-3

Starting from the tetrahydroisoquinoline SB-2770111, a novel series of 5-substituted-2,3-dihydro-1H-isoindoles has been designed. Subsequent optimisation resulted in identification of 19. which has high affinity for the dopamine D₃ receptor (pK_i 8.3) and ≥ 100-fold selectivity over other aminergic receptors. In rat studies 19 was brain penetrant with an excellent pharmacokinetic profile (oral bioavailability 77%. t_1/2 5.2h).

Full text of DOI:10.1016/S0960-894X(01)00037-3

Bioorganic & Medicinal Chemistry Letters 11 (2001) 685±688
Design and Synthesis of Novel 2,3-Dihydro-1H-isoindoles with
High Anity and Selectivity for the Dopamine D3 Receptor
Nigel E. Austin, Kim Y. Avenell, Izzy Boy®eld, Clive L. Branch,* Michael S. Hadley,
Phillip Je€rey, Christopher N. Johnson, Gregor J. Macdonald, David J. Nash,
Graham J. Riley, Alexander B. Smith, Geo€rey Stemp, Kevin M. Thewlis,
Antonio K. K. Vong and Martyn D. Wood
SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
Received 24 October 2000; revised 18 December 2000; accepted 8 January 2001
AbstractÐStarting from the tetrahydroisoquinoline SB-277011 1, a novel series of 5-substituted-2,3-dihydro-1H-isoindoles has been
designed. Subsequent optimisation resulted in identi®cation of 19, which has high anity for the dopamine D3 receptor (pKi 8.3)
and ꢀ100-fold selectivity over other aminergic receptors. In rat studies 19 was brain penetrant with an excellent pharmacokinetic
pro®le (oral bioavailability 77%, t1=2 5.2 h). # 2001 Elsevier Science Ltd. All rights reserved.
All clinically e€ective antipsychotic agents share the
property of dopamine D2 and D3 receptor antagonism.
Since these drugs occupy both D3 and D2 receptors at
clinical doses, their antipsychotic e€ects could be medi-
ated via D2 and/or D3 receptors. Blockade of D2 recep-
tors in the striatum leads to serious extrapyramidal side-
e€ects, resulting in poor patient compliance and there-
fore poor control of the disease. Interestingly, dopamine
D3 receptors are preferentially located in limbic brain
regions, such as the nucleus accumbens, where dopa-
mine receptor blockade has been associated with anti-
psychotic activity. Consequently, a selective dopamine
D3 receptor antagonist o€ers the potential for an e€ec-
tive antipsychotic therapy, free of the serious side-e€ects
of currently available drugs.1À4 The presence of the
dopamine D3 receptor in projection regions of the meso-
corticolimbic system also suggests a potential therapeutic
role in reinforcement processes and drug abuse.5
gested a good overlap between the 6-substituted-tetra-
hydroisoquinoline of 1 and 5-substituted-2,3-dihydro-
1H-isoindoles, such as 2 (Fig. 1). However, the model-
ling study also indicated the di€erent spatial require-
ments of the 2,3-dihydro-1H-isoindole, which might
adversely a€ect dopamine D3 anity. Accordingly, a
series of 5-substituted-2,3-dihydro-1H-isoindoles, rela-
ted to 1, has been synthesised and the structure±activity
relationship investigated, the results of which are
disclosed in this paper.
The synthesis of the starting 5-substituted-2,3-dihydro-
1H-isoindoles 3b±e is outlined in Scheme 1. Preparation
of 5-methanesulfonyloxy- and 5-cyano-2,3-dihydro-1H-
isoindoles 3b,c was accomplished via the key 5-hydroxy
intermediate 4, derived from 5-methoxy-2,3-dihydro-
1H-isoindole 3a7 by sequential O-demethylation and
N-protection. Reaction of 4 with methanesulfonyl chlo-
Recent reports from these laboratories have described
the design and synthesis of SB-277011 1, a potent and
selective dopamine D3 antagonist.6 As part of our con-
tinuing studies around SB-277011 1, it was important to
establish the e€ect on D3 anity and selectivity of
replacing the tetrahydroisoquinoline with a 2,3-dihydro-
1H-isoindole. Examination of molecular models sug-
*Corresponding author. Tel.: +44-1279-627734; fax: +44-1279-
627896; e-mail: clive_l_branch@sbphrd.com
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00037-3

686
N. E. Austin et al. / Bioorg. Med. Chem. Lett. 11 (2001) 685±688
ride or tri¯uoromethanesulfonic anhydride gave the
sulfonates 5 and 6, respectively. Palladium catalysed
reaction of 6 with Zn(CN)2 furnished the 5-cyano deri-
vative 7. Deprotection of 5 and 7 then a€orded the
required 2,3-dihydro-1H-isoindoles 3b,c. The 5-tri-
¯uoromethyl-2,3-dihydro-1H-isoindole 3e was obtained
from the 5-bromo intermediate 87 by reaction
with potassium tri¯uoroacetate in DMF, followed by
N-detosylation of 9 with 48% hydrobromic acid in the
presence of phenol and propionic acid. Similarly, 8
a€orded the 5-bromo analogue 3d.7
Transformation of the 2,3-dihydro-1H-isoindoles 3a±e
into the ®nal compounds 2 and 13±19 is outlined in
Scheme 2. Thus, reductive amination of the aldehyde
106 with the requisite 5-substituted-2,3-dihydro-1H-iso-
indole 3a±e in the presence of NaBH(OAc)3 a€orded
the corresponding protected amines 11a±e. N-Depro-
tection with TFA, followed by EDC-HOBt mediated
coupling of the resulting amines 12a±e with an appro-
priate acid provided the amides 2 and 13±19. All com-
pounds were puri®ed by chromatography and isolated
as their hydrochloride salts.
For direct comparison with the tetrahydroisoquinoline,
the ®rst derivative prepared and evaluated was the 5-
cyano-2,3-dihydro-1H-isoindole 2. Albeit less potent
than the corresponding tetrahydroisoquinoline SB-277011
1, the 5-cyano-2,3-dihydro-1H-isoindole analogue 2 had
encouraging anity for the D3 receptor (pKi 7.2) with
40-fold selectivity over the D2 receptor (Table 1). By
replacement of the 4-quinolinyl group by a 2-indolyl
Figure 1. Overlap of 5-cyano-2,3-dihydro-1H-isoindole (cyan) with
SB-277011 (magenta).
Scheme 1. Reagents: (i) 48% HBr, 100 ꢁC, 2 h, 80%; (ii) (Boc)2O, NEt3, CH2Cl2, rt, 16 h, 40%; (iii) MeSO2Cl, NEt3, CH2Cl2, rt, 16 h, 70%; (iv)
TFA, CH2Cl2, 40 ꢁC, 0.5 h, 90%; (v) (CF3SO2)2O, NEt3, CH2Cl2, À20 ꢁC±rt, 6 h, 70%; (vi) Zn(CN)2, Pd(PPh3)4, DMF, 100 ꢁC, 4 h, 90%; (vii)
CF3CO2K, CuI, DMF±PhMe, 110 ꢁC, 1.5 h, 90%; (viii) 48% HBr, PhOH, EtCO2H, 150 ꢁC, 6 h, 65%.
Scheme 2. Reagents: (i) NaBH(OAc)3, ClCH2CH2Cl, rt, 16 h, 55±85%; (ii) TFA, CH2Cl2, 40 ꢁC, 0.5 h, 90%; (iii) EDC, HOBt, CH2Cl2, rt, 16 h, 50±
90%.

N. E. Austin et al. / Bioorg. Med. Chem. Lett. 11 (2001) 685±688
687
group, as in compound 13, D3 anity was slightly
increased and 100-fold selectivity over the D2 receptor
was demonstrated. It had previously been observed in
the 6-cyano-tetrahydroisoquinoline series that a 4-
¯uorocinnamide moiety gave higher dopamine D3
receptor anity than the 4-quinolinylcarboxamide
group.6,10 This modi®cation to the acylamino moiety
identi®ed the trans-cinnamide 14, which had high a-
nity for the D3 receptor with a pKi of 7.9. Unfortu-
nately, D2 receptor anity also increased, with a slight
reduction in selectivity to 50-fold. Variation of the
phenyl substituent identi®ed the 3-methoxycinnamide
15, which ®rmly established that both high anity (pKi
8.0) for the D3 receptor and 100-fold selectivity over the
D2 receptor was achievable in this series. On cross-
screening against other aminergic receptors, cinnamide
15 was shown to be only 50-fold selective over the 5-
HT1D receptor. The reduced selectivity over the 5-HT1D
receptor observed in the 5-cyano-2,3-dihydro-1H-iso-
indole series was in contrast to the 6-cyano-tetra-
hydroisoquinoline series6 and may result from the
subtly di€erent spatial requirements of the 2,3-dihydro-
1H-isoindole and tetrahydroisoquinoline rings (see Fig.
1). With the aim of maintaining D3 anity and
improving the overall selectivity, alternative 5-sub-
stituted-2,3-dihydro-1H-isoindole
derivatives
were
investigated in the 4-¯uorocinnamide series. While the
5-tri¯uoromethyl- and 5-methoxy-analogues, 16 and 18
respectively, had similar D3 anity to the 5-cyano ana-
logue 14, the 5-bromo analogue 17 had increased D3
anity with a pKi of 8.5. These modi®cations however,
resulted in a similar enhancement of D2 receptor anity
and therefore only 25±40-fold selectivity over D2. In
previous studies on a series of 2-aminotetralin deriva-
tives, replacement of methoxy by methanesulfonyloxy
had maintained D3 anity and enhanced D2 selectiv-
ity.11 In agreement with this observation 19 demon-
strated excellent anity (pKi 8.3) for the D3 receptor,
and 100-fold selectivity over the D2 receptor. Further-
more, 19 had an excellent cross-screening pro®le, being
270-fold selective over the 5-HT1D receptor (pKi 5.9)
and ꢀ200-fold selective over other aminergic receptors
(pKi 5-HT1A 5.5, 5-HT1B 5.3, 5-HT2A <5.3, 5-HT2B
<6.0, 5-HT2C <5.1, 5-HT6 <5.0, 5-HT7 <5.4, a1B
<5.3). Studies in the in vitro functional assay9 showed
19 to be a potent antagonist at the D3 receptor with a
pKb of 8.3. In vivo evaluation in the rat demonstrated
that 19 was centrally penetrant (brain:blood 0.5:1) and
had an excellent pharmacokinetic pro®le, with high oral
bioavailability (77%), low clearance (CLb 14 mL/min/
kg) and long terminal half-life (t1=2 5.2 h).12
Table 1. Anities (pKi) of substituted 2,3-dihydro-1H-isoindole
derivatives at dopamine D3 and D2 receptors
Compounda
SB-277011
R1
Ð
R2
Ð
D3
D2
Selectivityc
100
b
b
8.0
7.2
6.0
5.6
Conclusions
2
NCÀ
NCÀ
40
100
50
Based on the tetrahydroisoquinoline SB-277011 1, a
novel series of 5-substituted-2,3-dihydro-1H-isoindoles
has been designed and structure±activity relationships
investigated. From this study, the 5-methanesulfonyloxy
derivative 19, with a binding anity (pKi 8.3) for the D3
receptor 2-fold higher than SB-277011 1 and with similar
100-fold selectivity over the D2 receptor, was identi®ed.
Furthermore it has been shown that 19 was ꢀ200-fold
selective over a package of 63 receptors and ion channels.
Additional studies established that 19 had an exceptional
pharmacokinetic pro®le and was also brain penetrant,
and therefore represents an excellent pharmacological
tool for the further characterisation of the role of the
dopamine D3 receptor in the central nervous system.
13
14
15
16
17
18
19
7.6
7.9
8.0
8.0
8.5
8.1
8.3
5.6
6.2
6.0
6.4
7.0
6.7
6.3
NCÀ
NCÀ
100
40
F3CÀ
BrÀ
35
MeOÀ
MeSO2OÀ
25
References and Notes
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100
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Wermuth, C. G.; Schwartz, J.-C.; Everitt, B. J.; Sokolo€, P.
Nature 1999, 400, 371.
aAll new compounds gave satisfactory analytical and/or mass spectral
data.8
bAll values represent the mean of at least 3 experiments, each within
0.3 of the mean.9
cSelectivity is de®ned as the antilogarithm of the di€erence between D3
and D2 pKi values.

688
N. E. Austin et al. / Bioorg. Med. Chem. Lett. 11 (2001) 685±688
6. Stemp, G.; Ashmeade, T.; Branch, C. L.; Hadley, M. S.;
Hunter, A. J.; Johnson, C. N.; Nash, D. J.; Thewlis, K. M.;
Vong, A. K. K.; Austin, N. E.; Je€rey, P.; Avenell, K. Y.;
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Coldwell, M. C.; Hadley, M. S.; Je€rey, P.; Johns, A.; John-
son, C. N.; Nash, D. J.; Riley, G. J.; Smith, S. A.; Stacey,
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8. 1H NMR spectra were recorded at 250 MHz in CDCl3 as
solvent. Compound 19 mp 264±266 ꢁC (HCl salt); (Found: C,
59.6; H, 6.1; N, 5.3; m/z 487 (MH+). C26H31FN2O4S requires
C, 59.7; H, 6.2; N, 5.4%, M486); 1H NMR (free base): d 1.05±
1.30 (m, 5H), 1.40±1.54 (m, 2H), 1.80±1.90 (m, 2H), 2.00±2.15
(m, 2H), 2.74 (t, J=7 Hz, 2H), 3.12 (s, 3H), 3.86 (m, 1H), 3.90
(m, 4H), 5.45 (d, J=8 Hz, 1H), 6.27 (d, J=16 Hz, 1H), 7.00±
7.20 (m, 5H), 7.47 (m, 2H), 7.57 (d, J=16 Hz, 1H).
9. Compounds were evaluated in binding assays using dis-
placement of 125I-iodosulpride from human D3 and D2 recep-
tors, expressed in CHO cells. Functional activity of compound
19 was determined in vitro using microphysiometry. Apparent
pKb values were D3 (8.3) and D2 (6.7). For details see Boy®eld,
11. Boy®eld, I.; Coldwell, M. C.; Hadley, M. S.; Johnson,
C. J.; Riley, G. J.; Scott, E. E.; Stacey, R.; Stemp, G.; Thewlis,
K. M. Bioorg. Med. Chem. Lett. 1997, 7, 1995.
12. CNS penetration at steady-state was investigated in the
rat. The compound was dissolved in 2% (v/v) DMSO in 5%
(w/v) dextrose aq and administered at a constant infusion rate
over 12 h at a target dose rate of 0.3 mg free base/kg/h. Blood
samples were removed during the latter part of the infusion to
con®rm steady-state blood concentrations. Blood and brain
samples were analysed by LC/MS/MS. Values for blood
clearance (CLb) were determined according to the relation-
ship CLb=infusion rate/steady-state blood concentration
(Css).