Novel pyridyl-fused 3-amino chroman derivatives with dual action at serotonin transporter and 5-HT1A receptor

Article abstract of DOI:10.1016/j.bmcl.2007.03.049

Structural modifications of the initial lead, 3-aminochroman (4), led to the identification of a novel series of pyridyl-fused amino chroman derivatives (5-8) and the structural isomers (9-12). The compounds described were evaluated for dual 5-HT transpor

Full text of DOI:10.1016/j.bmcl.2007.03.049

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3117–3121
Novel pyridyl-fused 3-amino chroman derivatives with dual action
at serotonin transporter and 5-HT1A receptor
Dahui Zhou,a,* Nicole T. Hatzenbuhler,a Jonathan L. Gross,a Boyd L. Harrison,a
Deborah A. Evrard,a Michael Chlenov,a Jeannette Golembieski,b Geoffrey Hornby,b
Lee E. Schechter,b Deborah L. Smith,b Terrance H. Andreeb and Gary P. Stacka
aChemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA
bNeuroscience Discovery Research, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA
Received 15 February 2007; revised 12 March 2007; accepted 12 March 2007
Available online 19 March 2007
Abstract—Structural modifications of the initial lead, 3-aminochroman (4), led to the identification of a novel series of pyridyl-fused
amino chroman derivatives (5–8) and the structural isomers (9–12). The compounds described were evaluated for dual 5-HT trans-
porter inhibitory and 5-HT1A receptor activities. The design strategy, synthesis, and in vitro biological characterization for these
novel compounds are described.
Ó 2007 Elsevier Ltd. All rights reserved.
Selective serotonin reuptake inhibitors (SSRIs) are effec-
tive antidepressants with fewer side effects than the older
tricyclics. SSRIs work by blocking the neuronal reup-
take of serotonin, thereby increasing the concentration
of serotonin in the synaptic space, and thus increasing
the activation of postsynaptic serotonin receptors. How-
ever, long-term treatment is required before clinical effi-
cacy is achieved.1,2 It has been suggested that the SSRIs
increase the serotonin levels in the vicinity of the seroto-
nergic cell bodies and that excess serotonin activates
somatodendritic 5-HT1A autoreceptors that decrease
neuron firing to release serotonin in the forebrain. A
5-HT1A antagonist would limit the negative feedback
and should improve the efficacy of the serotonin reup-
take mechanism. Co-administration of a 5-HT1A recep-
tor antagonist and a SSRI has been shown to accelerate
antidepressant effects.3,4 Therefore, the concept of devel-
oping a dual-acting agent blocking both the 5-HT1A
receptor and 5-HT reuptake site in one molecule has
been proposed. Several groups have already reported
their efforts and design strategies toward constructing
new agents with 5-HT1A receptor antagonist and 5-HT
reuptake inhibitor properties.5–9
Previous reports from our laboratories have revealed a
dual-ligand approach to incorporate both a 5-HT trans-
porter and 5-HT1A receptor pharmacophore within a sin-
gle molecule. Amalgamation of a 5-fluoroindole alkyl
amine (1)5 and a 3-aminochroman (2)10 through the com-
mon basic nitrogen (Fig. 1) provided racemic N-(3-(5-flu-
oro-1H-indol-3-yl)propyl)-5-methoxy-N-propylchroman-
3-amine (4) as an initial lead.11 As a continuation of this
effort, structural modifications were focused on the 3-ami-
nochroman ring present in 4, with the aim of improving
affinity for the 5-HT1A receptor and 5-HT transporter
while reducing intrinsic activity at the 5-HT1A receptor.
Herein, we report our design strategy, the synthesis, and
corresponding biological activities of compounds
represented by the 2,3-dihydro-1H-pyrano[3,2-f]-quino-
lin-2-amine core 5–8 and the constitutionally isomeric
3,4-dihydro-2H-pyrano[2,3-f]quinolin-3-amine core 9–12.
Inspired by our previous results with heterocycle-fused
benzodioxane analogs that demonstrated potent dual
activity as both 5-HT transporter inhibitors and 5-HT1A
receptor antagonists,12 we elected to replace the pendant
methoxy group on the 3-aminochroman in 4 with a fused
pyridine ring. We envisioned this modification would
serve a dual role; that the nitrogen in the pyridine would
serve as a conformationally constrained hydrogen bond
acceptor, a recognized feature of the 5-HT1A pharmaco-
phore,13 and that the tricyclic ring scaffold would reduce
the intrinsic activity at the 5-HT1A receptor.
Keywords: Serotonin transporter; 5-HT1A receptor.
*
Corresponding author. Tel.: +1 732 274 4423; fax: +1 732 274
4505; e-mail: zhoud@wyeth.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.03.049

3118
D. Zhou et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3117–3121
F
OCH3
N
NH2
O
HN
2 (5-HT1A receptor agonist)
1 (5-HT reuptake ligand)
R1
N
NH
OCH3
3-4, R1 = H, n-Pr
O
F
5-HT1A activity 5-HT reuptake activity
R1
N
NH
R1
NH
N
N
n
n
N
O
F
O
F
5-8, n= 0 and 1; R1 = H, n-Pr
9-12, n= 1 and 2; R1 = H, n-Pr
Figure 1. Design strategy.
OH
a
O
OH
b
c
N
N
N
15
13
16
19
14
Br
OH
OAc
OH
OH
f
e
OBn
OBn
d
N
N
N
N
18
17
OH
O
OTs
OAc
h
O
g
i
O
N
N
20
21
NH2
N3
H
N
H
O
j
O
k
N
N
n
N
N
O
F
23
5, n = 1
7, n = 0
22
H
N
l
N
N
n
O
F
6, n = 1
8, n = 0
Scheme 1. Reagents and conditions: (a) allyl bromide/NaH, rt, 89%; (b) p-xylene, reflux, 72%; (c) BnCl/NaH, rt, 92%; (d) AD-mix-a/t-BuOH Æ H2O,
rt, 88%; (e) 33% HBr/HOAc, 60 °C, 65%; (f) NaH/DMF, 61%; (g) K2CO3/MeOH, rt, 91%; (h) TsCl/Py, rt, 93%; (i) NaN3/DMF, 60 °C, 77%;
(j) Ph3P/THF–H2O, rt, 70%; (k) 5-fluoro-3-indolepropyl-bromide or 5-fluoro-3-indoleethyl bromide/Et3N/DMSO, 90 °C, 38–64%;
(l) CH3CH2CHO/NaCNBH3/HOAc/MeOH, rt, 45–77%.
The synthesis of compounds 5–8 (Scheme 1) began with
the formation of 6-allyloxy-quinoline (14) from commer-
cially available 6-hydroxyquinoline (13). Subsequent
Claisen rearrangement produced 5-allyl-quinolin-6-ol
(15). Following benzyl protection of the phenol present
in 15, Sharpless catalytic dihydroxylation14 afforded

D. Zhou et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3117–3121
3119
a
b
c
N
OH
Br
N
O
N
OH
26
AcO
24
25
OH
HO
f
e
d
N
N
OBn
N
OBn
N
OH
27
29
28
OTs
OAc
g
OH
h
i
N
O
O
N
O
H
31
32
30
N
H
N
N3
j
NH2
k
n
N
O
N
O
N
O
F
9, n = 1
11, n = 2
33
34
H
N
l
N
n
N
O
F
10, n = 1
12, n = 2
Scheme 2. Reagents and conditions: (a) allyl bromide/NaH, rt, 85%; (b) p-xylene, reflux, 48%; (c) BnCl/NaH, rt, 100%; (d) AD-mix-a/t-BuOH Æ H2O,
rt, 94%; (e) 30% HBr/HOAc, 60 °C, 66%; (f) NaH/DMF, 67%; (g) K2CO3/MeOH, rt, 81%; (h) TsCl/Py, rt, 59%; (i) NaN3/DMF, 60 °C, 68%;
(j) Ph3P/THF–H2O, rt, 68%; (k) 5-fluoro-3-indolepropyl-bromide or 5-fluoro-3-indolebutyl chloride/Et3N/DMSO, 90 °C; 18–74%;
(l) CH3CH2CHO/NaCNBH3/HOAc/MeOH, rt, 36–90%.
3-(6-benzyloxy-quinolin-5-yl)-propane-1,2-diol
17.
5-HT1A receptor (h-5-HT1A) as well as 5-HT1A receptor
intrinsic activity ([35S]-GTPcS Emax). Additionally, since
the receptor binding pharmacology for the 5-HT1A
receptor exhibits significant overlap with the a1 recep-
tor,15 the a1 receptor affinity for compounds 3–12 was
also determined.
Treatment of 17 with 33% hydrogen bromide in acetic
acid provided the acetoxy bromide (18). Ring closure
was carried out in DMF using sodium hydride to
generate the chroman 19. Removal of the acetyl group
under the basic condition produced 2,3-dihydro-1H-pyr-
ano[3,2-f]quinolin-2-ol (20). Formation of the tosylate 21
was followed by conversion to azide 22. Reduction of the
azide (22) to the amine 23 using triphenylphosphine in
THF–H2O followed by coupling with an appropriate in-
dole alkyl bromide afforded the secondary amines ( )-5
and ( )-7. The corresponding N-propyl derivatives
( )-6 and ( )-8 were generated by reductive amination
with propionaldehyde. Utilizing chiral HPLC, resolution
of ( )-5 provided the corresponding enantiomers in
99% ee. In a similar fashion to that described for the
racemates, reductive amination of (+)-5 and (À)-5
provided (+)-6 and (À)-6 in optically pure form.
Comparison of 5-methoxy-3,4-dihydro-2H-1-benzopy-
ran analog ( )-3 and 2,3-dihydro-1H-pyrano[3,2-f]quin-
olin-2-amine ( )-5 demonstrated a 4-fold improvement
in 5-HT-T affinity, while the affinity at the 5-HT1A
receptor remained the same (Table 1). Resolution of
( )-5 identified the (+)-enantiomer as the eutomer with
respect to both 5-HT1A receptor and 5-HT-T affinity;
(+)-5 exhibited a 13-fold increase in affinity for the
5-HT1A receptor and 4-fold increase in affinity for the
5-HT transporter when compared to its corresponding
enantiomer. However, the a1 affinity appeared to reside
in the (À)-enantiomer as (+)-5 was observed to be more
selective over the a1 receptor. Unfortunately, the intro-
duction of additional substitution (n-propyl) on the
basic nitrogen of ( )-5 led to a decrease in 5-HT
transporter affinity [( )-6 vs. ( )-5] albeit without a
corresponding decrease in 5-HT1A receptor binding.
Utilizing 5-hydroxyquinoline (24) and following the
same general synthetic sequence described above, the de-
sired products ( )-9 and ( )-10 were isolated (Scheme 2).
Resolution of ( )-9 into its respective enantiomers using
chiral HPLC provided (+)-9 and (À)-9 in 99% ee, respec-
tively. The intermediate 34 was also coupled to indole
butyl chloride to afford the secondary amine ( )-11.
The corresponding N-propyl derivative ( )-12 was
generated by reductive amination with propionaldehyde.
Shortening the length of the aminoalkyl tether between
the indole and chroman resulted in decreased affinity
for both the 5-HT1A receptor and 5-HT transporter
[( )-7 vs. ( )-5]. As previously observed, alkylation of
the basic nitrogen present in ( )-7 resulted in a further
decrease in affinity [( )-8].
Compounds were evaluated in vitro to determine affinity
for both the serotonin transporter (r-5-HT-T) and

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D. Zhou et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3117–3121
Table 1. Binding affinities at 5-HT transporter, 5-HT1A receptor, and a1-adrenoceptor for compounds 3–12a
R1
NH
R1
N
NH
N
n
N
n
N
O
F
O
5-8
9-12
F
Compound
R1
n
r-5-HT-T Kib (nM)
h-5-HT1A Kic (nM)
r-a1 Kid (nM)
( )-3
( )-4
( )-5
(+)-5
(À)-5
( )-6
(À)-6
(+)-6
( )-7
( )-8
( )-9
(+)-9
(À)-9
( )-10
( )-11
( )-12
H
1
1
1
1
1
1
1
1
0
0
1
1
1
1
2
2
9.2
9
70.4
15.8
772.5
820
n-Pr
H
2.4
1.3
5.1
16.9
8.8
19.8
30.5
62.8
2.6
3
62.6
23.9
324.2
590.8
221
H
H
313.8
63.5
n-Pr
n-Pr
n-Pr
H
18% at 1 lM
31% at 1 lM
38% at 1 lM
1078.7
209.6
58
10% at 1 lM
477.8
105.1
n-Pr
H
711.2
489.5
H
392
67.8
623.7
387.7
H
1.2
12.4
1.5
12
n-Pr
H
46% at 1 lM
47% at 1 lM
21% at 1 lM
1234.3
33% at 1 lM
19% at 1 lM
n-Pr
a Ki values are means of at least two experiments SEM (performed in triplicate, determined from nine concentrations) and all Ki values were
calculated from IC50 values using the method of Cheng and Prusoff.16
b Binding affinity at rat cortical 5-HT reuptake sites labeled with [3H]-paroxetine.17
c Binding affinity at human 5-HT1A receptors in CHO cells labeled with [3H]-8-OH-DPAT.18
d Binding affinity at rat cortical a1 adrenergic receptors labeled with [3H]-prazosin.19
The constitutional isomer ( )-9 also demonstrated an
improvement in affinity for the 5-HT1A receptor (5-fold)
and 5-HT-T (3-fold) when compared to the incipient
chroman analog ( )-3. Extending the aminoalkyl tether
[( )-11] resulted in small improvement in 5-HT-T affinity.
However, the four-carbon tether compound showed a sig-
nificant decrease in 5-HT1A receptor affinity [( )-11 vs.
( )-9]. Unlike the improvement in 5-HT-T affinity exhib-
ited by ( )-4 upon alkylation of the secondary amine pres-
ent in ( )-3, the introduction of an n-propyl substituent to
secondary amines ( )-9 and ( )-11 resulted in decreased
affinity for the 5-HT1A receptor [( )-10 vs. ( )-9 and
( )-12 vs. ( )-11]. In general, all the compounds demon-
strated good selectivity over the a1 receptor.
Table 2. Functional activity at 5-HT1A receptor
R1
NH
N
N
O
O
5-6
F
F
R1
N
NH
N
9
Compound
R1
h-5-HT1A GTPcS Emax (EC50a nM)
(+)-5
(À)-5
(À)-6
(+)-6
(+)-9
(À)-9
H
100 (181.8)
86 (116.2)
55 (628.6)
100 (301.2)
75 (332.4)
100 (171.60)
H
n-Pr
n-Pr
H
The 5-HT1A receptor functional activity was obtained for
the enantiomeric pairs of 5, 6, and 9 (Table 2). For the
enantiomers of the secondary amines 5 and 9 there was
little, if any, separation of the intrinsic activity elicited
at the 5-HT1A receptor. However, the influence of the ste-
reogenic center present in 6 had a significant impact on
function with (À)-6 demonstrating partial agonist
(55%) activity at the 5-HT1A receptor. Unfortunately,
the affinity for the 5-HT1A receptor resided with (+)-6.
H
a Stimulation of GTPcS35 binding in CHO cells expressing 5-HT1A
receptor;20 Emax refers to maximal agonist effect relative to 5-HT.
ued efforts are focused on developing our understanding
of how to resolve this dichotomy in the design of novel
molecules with dual 5-HT1A receptor antagonism and
5-HT reuptake inhibitory activity.
In conclusion, the secondary amine analogs demon-
strated greater affinity for both the serotonin transporter
and the 5-HT1A receptor than their corresponding ter-
tiary amine analogs. A three-carbon tether between the
indole and aminochroman was optimal for affinity. As
observed with compound (À)-6, contrary to the effect
on binding, the presence of a tertiary amine appeared
critical for the ability to modulate function. Our contin-
Acknowledgments
The authors thank the members of the Wyeth Chemical
Technology Department for their assistance in the struc-
tural confirmation of the compounds described in this
letter.

D. Zhou et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3117–3121
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