Synthesis and hSERT activity of homotryptamine analogs. Part 6: [3+2] dipolar cycloaddition of 3-vinylindoles

Article abstract of DOI:10.1016/j.bmcl.2009.12.043

Substituted 1-tosyl-3-vinylindoles undergo [3+2] dipolar cycloaddition with cyclic nitrones to afford substituted isoxazoles in good yield and high diastereoselectivity. The cycloadducts were readily converted in 4 steps into ring constrained homotryptamine analogs. These analogs exhibited excellent binding affinity for the human serotonin transporter (hSERT). Indoles bearing a 5-cyano group and a pendent ethyl(tetrahydroisoquinoline) moiety at the 3-position displayed the best potency for hSERT and high selectivity versus hDAT and hNET.

Full text of DOI:10.1016/j.bmcl.2009.12.043

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1027–1030
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and hSERT activity of homotryptamine analogs. Part 6: [3+2] dipolar
cycloaddition of 3-vinylindoles
*
Lawrence R. Marcin , Ronald J. Mattson, Qi Gao, Dedong Wu, Thaddeus F. Molski, Gail K. Mattson,
Nicholas J. Lodge
Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted 1-tosyl-3-vinylindoles undergo [3+2] dipolar cycloaddition with cyclic nitrones to afford
substituted isoxazoles in good yield and high diastereoselectivity. The cycloadducts were readily con-
verted in 4 steps into ring constrained homotryptamine analogs. These analogs exhibited excellent bind-
ing affinity for the human serotonin transporter (hSERT). Indoles bearing a 5-cyano group and a pendent
ethyl(tetrahydroisoquinoline) moiety at the 3-position displayed the best potency for hSERT and high
selectivity versus hDAT and hNET.
Received 14 October 2009
Revised 4 December 2009
Accepted 10 December 2009
Available online 16 December 2009
Keywords:
Homotryptamine
Serotonin
SERT
Ó 2009 Elsevier Ltd. All rights reserved.
DAT
NET
SSRI
Dipolar cycloaddition
3-Vinylindole
Nitrone
Inhibition of the human serotonin reuptake transporter (hSERT)
has proven utility for the treatment of depression and other related
affective disorders, including anxiety, social phobia, obsessive–
compulsive and panic disorders.1 Consequently, the discovery
and development of novel selective serotonin reuptake inhibitors
(SSRIs) continues to be an active field of neuroscience research.2
A series of manuscripts3 has previously disclosed hSERT binding
data for homotryptamine derivatives, including compound 1,3a
and has detailed our efforts to engineer conformationally restricted
analogs with optimized hSERT potency and target selectivity, such
as indoles 2,3b 3,3c and 4,3e (Fig. 1). As part of an ongoing medicinal
chemistry effort, we targeted 3-indolylethylamines 5, in which the
privileged homotryptamine-like scaffold is conserved and the pen-
dant amino group is embedded or constrained within a heterocy-
clic ring system ( Fig. 2). Early literature reports have disclosed
that some 2-(3-indolylethyl)piperidines, and closely related ana-
logs, possess useful central nervous system (CNS) activity;4 how-
ever, characterization of their hSERT activity is absent. This
communication describes a novel and expedient synthesis of sev-
eral 2-(3-indolyl)ethylamines and a structure activity relationship
(SAR) of their binding affinity for hSERT.
2-(3-Indolylethyl)piperidines and related molecules have been
made by a few different methods including Knoevenagel condensa-
tion of indole carboxaldehydes5 and pyridylethylation of indoles.6
We had envisioned a more flexible retrosynthetic strategy in which
the final products 5 are unmasked via hydrogenolysis/deoxygen-
ation of bicyclic isoxazoles 6. The isoxazoles 6 would result from
[3+2] dipolar cycloaddition of cyclic nitrones 8 with 3-vinylindoles
7. The choice of cyclic nitrone would dictate the nature of the final
NC
NC
N
N
N
N
H
H
1
2
N
NC
NC
N
N
H
N
H
3
4
* Corresponding author. Tel.: +1 203 677 6701; fax: +1 203 677 7702.
E-mail address: Lawrence.marcin@bms.com (L.R. Marcin).
Figure 1. Known indole-based SERT ligands.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.043

1028
L. R. Marcin et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1027–1030
X
X
N
O
[H]
R'
N
R1
R'
N
X = O, CH2, bond
N
H
PG
6
5
[3+2] dipolar
cycloaddition
R'
X
+
N
O
N
PG
Figure 3. ORTEP drawing of 12 with thermal ellipsoids at 25% probability for non-H
atoms and open circles for H-atoms.
7
8
Figure 2. Retrosynthetic analysis of 3-indolylethylamines.
azole 10 in 84% yield (Scheme 1). The relative stereochemistry of
10 was inferred from single crystal X-ray analysis of the corre-
sponding aminal derivative 12 (Fig. 3).9 The stereochemical out-
come of the dipolar cycloaddition is consistent with an exo-mode
approach of the dipolarophile and is in full agreement with litera-
ture reports for the dipolar cycloaddition of styrene with 2,3,4,5-
tetrahydropyridine 1-oxide.7a Isoxazole 10 was readily converted
in a routine 4-step sequence to a series of 2-(3-indolylethyl)piper-
idines 14a–f. The nature of the piperidine N-substituent was
dependent on the choice of aldehyde used in the reductive amina-
tion.10 The final products 14a–f were obtained in good overall yield
(ꢀ25–40%).
pendent amine. While there is no literature precedent for the [3+2]
dipolar cycloaddition of 3-vinylindoles with nitrones, styrene has
been reported to undergo highly regio- and diastereoselective
dipolar cycloadditions with 2,3,4,5-tetrahydropyridine 1-oxide
and 3,6-dihydro-2H-1,4-oxazine 4-oxide.7 Given our previous
experience with 3-vinylindoles as useful substrates in catalytic
asymmetric cyclopropanation,8 we expected that the proposed
dipolar cycloaddition chemistry would proceed smoothly.
5-Cyanoindole was selected as the aromatic core for the current
set of targets, because this substitution pattern provided optimal
hSERT binding affinity in the related indole cyclopropane series.3b
To our gratification, 5-cyano-1-tosyl-3-vinylindole 9a8 was found
to undergo [3+2] dipolar cycloaddition at room temperature in
Piperidine derivatives 15a and 15b and analogs 16a and 16b
were prepared in analogous fashion from 6-methyl-2,3,4,5-tetra-
hydropyridine 1-oxide and 4-benzyl-2,3,4,5-tetrahydropyridine
1-oxide (Fig. 4).11 It should be noted that the dipolar cycloaddition
in the synthesis of 15a, which forms a quaternary center, pro-
ceeded in diminished yield (32%) as compared to the related cyclo-
addition of 8 with 9a (84%). Morpholine adduct 17 and pyrrolidine
analogs 18a,b were also prepared in a regio- and stereoselective
fashion following the same multistep sequence and starting with
the appropriate nitrones.11
the presence of 4 equiv of 2,3,4,5-tetrahydropyridine 1-oxide7a
8
to afford a single diastereomer of the corresponding bicyclic isox-
H
NC
N
O
NC
a
c
f
H
+
The dipolar cycloaddition of conjugated nitrones also proceeded
N
well. For example, 3,4-dihydroisoquinoline 2-oxide (19)11 under-
N
O
4 equiv
8
Ts
N
Ts
9a
10
Ph
b
N
NC
R1
H
N
R1
(77 %)
N
NC
HO
N
H
NC
NC
(32 %)
H
O
N
H
15a, R = H
15b, R = CH3
N
H
16a, R = H
16b, R = CH3
N
N
Ts
12
11
Ts
O
d, e
N
NC
N
R1
NC
R1
HO
N
R1
N
R1
NC
NC
N
H
(57 %)
(36 %)
N
H
N
N
18a, R = H
18b, R = CH3
17
14a-f
H
H
13a-f
Scheme 1. Reagents and conditions: (a) ClCH2CH2Cl, rt, 48 h (84%); (b) Zn, HOAc;
(c) CH2O, EtOH, H2O (63%, 2 steps); (d) RHCO, NaCNBH3, THF, EtOH; (e) NaOH, EtOH,
H2O, 65 °C; (f). TFA, (C2H5)3SiH, CH2Cl2, 0 °C (38% over 4 steps for 14a).
Figure 4. Various 2-(3-indolylethyl)heterocycles prepared from dipolar cycloaddi-
tion of nitrones with 5-cyano-1-tosyl-3-vinylindole. Yield of the [3+2] dipolar
cycloaddition step is shown in parentheses.

L. R. Marcin et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1027–1030
1029
Table 2
Binding affinity for selected monoaminergic transporters
R2
a
b
b
Compound
SERT IC50 (nM)
hDAT IC50 (nM)
hNET IC50 (nM)
a
+
1
2
3
4
2.0 0.4
nt
nt
9200
390
7900
>10,000
N
O
0.36 0.05
0.72 0.11
0.13 0.07
0.42 0.06
4200
290
690
620
N
Ts
3 equiv
19
9a-c
(À)-21a
a
Values are means of P3 experiments with SEM.
Values are the average of 2 experiments. (nt = not tested).
b
H
R2
N
N
O
R2
H
N
b, c, d, e
Table 2 summarizes the binding affinity of compound (–)-21a
and previously reported analogs 1–4 for hSERT and the other amin-
ergic transporters, hDAT (dopamine) and hNET (norepinephrine).
The hSERT binding affinity of (–)-21a is approximately fivefold
greater than that reported for the open chain analog 1 and similar
in magnitude to the conformational restricted analogs 2–4. A
broader comparison reveals that analogs 14–18 displayed equal
or weaker affinity for hSERT versus the flexible analog 1. Conse-
quently, the enhanced potency of (–)-21a versus 1 for hSERT is
not likely the result of the pendent amine being constrained in a
six-membered ring, but more likely due to favorable interactions
with the second aromatic ring (1,2,3,4-tetrahydroquinoline) and
the serotonin transporter. Indeed, several marketed SSRIs, includ-
ing Fluoxetine, Paroxetine, Sertraline and S-citalopram contain
two aromatic rings in addition to the basic amine. Compound
(–)-21a demonstrated excellent selectivity for hSERT versus hDAT
(1500-fold) and hNET (>20,000-fold). This magnitude of selectivity
is similar to that observed with previous ring-constrained analogs
2 and 4.
In conclusion, a novel and flexible route to 2-(3-indolyl)ethyl-
amines was developed which employs a [3+2] dipolar cycloaddi-
tion of 3-vinylindoles and cyclic nitrones as the key bond-
forming event. While ring constrained 2-(3-indolyl)ethylamines
14–18 demonstrated good hSERT binding affinity, the level of po-
tency is not generally superior to the flexible N,N-dimethyl analog
1. The tetrahydroisoquinoline (–)-21a displayed subnanomolar po-
tency for hSERT and excellent selectivity against hDAT and hNET.
Continued efforts to optimize hSERT potency of the 2-(3-indo-
lyl)ethylamines will be focused on determining the absolute con-
figuration of (–)-21a and developing additional SAR for
tetrahydroisoquinoline substitution as well as the exploration of
other benzylic pendent amines.
21a, R' = CN
21b, R' = F
21c, R' = OCH3
N
H
20a-c
Ts
Scheme 2. Reagents and conditions: (a) toluene, reflux, 24 h (61–74%); (b) Zn,
HOAc; (c) H2CO, NaCNBH3, THF, EtOH; (d) NaOH, EtOH, H2O, 65 °C; (e) TFA,
(C2H5)3SiH, CH2Cl2, 0 °C (17–50%, 4 steps).
went dipolar cycloaddition, in refluxing toluene, with 5-cyano, 5-
fluoro, and 5-methoxy-1-tosyl-3-vinyl indoles 9a–c8 to afford the
corresponding tricyclic isoxazoles 20a–c in 61–74% yield (Scheme
2). The isoxazoles were subsequently transformed via the standard
4-step sequence into tetrahydroisoquinoline analogs 21a–c (17–
50% yield). The 5-cyanoindole derivative 21a was separated into
its individual enantiomers, (+)-21a and and (–)-21a, by preparative
chiral HPLC.12
All of the final analogs 14–18 and 21 demonstrated potent
hSERT binding with IC50 values 6 120 nM (Table 1).13 A number
of piperidine and tetrahydroisoquinoline analogs demonstrated
the best potency. The most potent analog was the single enantio-
mer (–)-21a (hSERT IC50 = 0.42 nM), which exhibited a binding
affinity for hSERT that was sixfold more potent than that observed
with the marketed SSRI Fluoxetine. The 5-fluoroindole 21b was
approximately fivefold less potent than 21a, while the 5-methoxy-
indole 21c lost over 100-fold in hSERT potency. Within the piperi-
dine series, analogs with electron-deficient N-alkyl substituents
displayed diminished SERT affinity, as exemplified by 14d and
14f. The less basic morpholine derivative 17 also exhibited weaker
SERT binding. These SAR trends are similar to those previously ob-
served in the indole cyclopropane series.3b
Table 1
Binding affinity for hSERT of analogs 14–18 and 21
References and notes
R1
R2
—
hSERT IC50 (nM)
a
Compound
Amine type
1. Spinks, D.; Spinks, G. Curr. Med. Chem. 2002, 9, 799.
Fluoxetine
14a
14b
14c
14d
14e
14f
15a
15b
16a
16b
17
18a
18b
21a
(+)-21a
(À)-21a
21b
Acyclic
—
H
2.5 0.5
2.5 0.2
3.9 0.3
4.0 0.7
80 25
2. Lopez-Munoz, F.; Cecilio, A. Curr. Pharm. Des. 2009, 15, 1563.
3. (a) Schmitz, W. D.; Denhart, D. J.; Brenner, A. B.; Ditta, J. L.; Mattson, R. J.;
Mattson, G. K.; Molski, T. F.; Macor, J. E. Bioorg. Med. Chem. Lett. 2005, 15, 1619;
(b) Mattson, R. J.; Catt, J. D.; Denhart, D. J.; Deskus, J. A.; Ditta, J. L.; Higgins, M.
A.; Marcin, L. R.; Sloan, C. P.; Beno, B. R.; Gao, Q.; Cunningham, M. A.; Mattson,
G. K.; Molski, T. F.; Taber, M. T.; Lodge, N. J. J. Med. Chem. 2005, 48, 6023; (c)
Deskus, J. A.; Epperson, J. R.; Sloan, C. P.; Cipollina, J. A.; Dextraza, P.; Qian-
Cutrone, J.; Gao, Q.; Ma, B.; Beno, B. R.; Mattson, G. K.; Molski, T. F.; Krause, R.
G.; Taber, M. T.; Lodge, N. J.; Mattson, R. J. Bioorg. Med. Chem. Lett. 2007, 17,
3099; (d) King, H. D.; Denhart, D. J.; Deskus, J. A.; Ditta, J. L.; Epperson, J. R.;
Higgins, M. H.; Kung, J. E.; Marcin, L. R.; Sloan, C. P.; Mattson, G. K.; Molski, T. F.;
Krause, R. G.; Bertekap, R. L., Jr.; Lodge, N. J.; Mattson, R. J.; Macor, J. E. Bioorg.
Med. Chem. Lett. 2007, 17, 5647; (e) Denhart, D. J.; Deskus, J. A.; Ditta, J. L.; Gao,
Q.; King, D.; Kozlowski, E. S.; Meng, Z.; LaPaglia, M. A.; Mattson, G. K.; Molski, T.
F.; Taber, M. T.; Lodge, N. J.; Mattson, R. J.; Macor, J. E. Bioorg. Med. Chem. Lett.
2009, 19, 4031.
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Morpholine
Pyrrolidine
Pyrrolidine
THQb
CH3
CH2CH3
CH2CH2CF3
CH2C6H5
3,5-Bis(CF3)Bn
H
CH3
H
CH3
—
H
CH3
—
—
—
7.0 1.8
46
17
5
2
2.1 0.4
18
7.6 1.2
3
76
17
5
3
8.1 2.1
1.1 0.2
4.2 0.5
0.42 0.06
5.7 1.3
120 11
CN
CN
CN
F
THQb
4. (a) Gray, A.; Kraus, H. J. Org. Chem. 1961, 26, 3368; (b) Lehmann, A.; Fless, D. A.
Psychopharmacologia 1962, 3, 331.
5. Castle, R. N.; Whittle, C. W. J. Org. Chem. 1959, 24, 1189.
THQb
THQb
—
—
21c
THQb
OCH3
6. Gray, A. P.; Archer, W. L. J. Am. Chem. Soc. 1957, 79, 3554.
7. (a) Ali, A.; Wazeer, M. I. M. J. Chem. Soc., Perkin Trans. 1 1998, 597; (b) Ali, A.;
Almuallem, H. A. Tetrahedron 1992, 48, 5273.
8. Marcin, L. R.; Denhart, D. J.; Mattson, R. J. Org. Lett. 2005, 48, 2651.
a
Values are means of P3 experiments with SEM.
THQ is an abbreviation for 1,2,3,4-tetrahydroisoquinoline.
b

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L. R. Marcin et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1027–1030
9. Full crystallographic data have been deposited to the Cambridge
Crystallographic Data Center (CCDC reference number 749351). Copies of the
data can be obtained free of charge via the internet at www.ccdc.cam.ac.uk/.
10. When R = H, the reductive amination step was omitted.
11. The cyclic nitrones used in the preparation of 15–18 and 20 were prepared
from their corresponding amines following the published method Murahashi,
S.-I.; Shiota, T.; Imada, Y. Org. Syn. 1992, 70, 265.
data for (–)-21a: LC–MS (M+H)+ = 316.2; 1H NMR (400 MHz, d6-DMSO) d 11.4
(s, 1H), 7.92 (s, 1H), 7.48 (d, 1H, J = 8.5), 7.39 (dd, 1H, J = 8.5,1.6), 7.32 (s, 1H),
7.16–7.10 (m, 4H), 3.49 (m, 1H), 3.16–3.10 (m, 1H), 2.85–2.60 (m, 4H), 2.56–
2.52 (m, 1H), 2.42 (s, 3H), 2.12–2.05 (m, 2H). Optical rotation: [
a
]
À1.37
D
(concentration = 4.23 mg/mL, CH3OH). Anal. Calcd for C21H21N3Á1/3H2O: C,
78.47; H, 6.79; N, 13.07. Found: C, 78.69; H, 6.67; N, 13.01.
13. hSERT, hDAT, and hNET binding affinities were determined as previously
described in Ref. 3e using membrane homogenates from stably transfected
HEK-293 cell lines expressing the human form of the transporters.
12. Chiralcel OD column (0.05% diethylamine/4.95% ethanol/95% hexanes). The
first enantiomer to elute was (+)-21a and the second was (–)-21a. Analytical