N-Alkyl-N-arylmethylpiperidin-4-amines: Novel dual inhibitors of serotonin and norepinephrine reuptake

Article abstract of DOI:10.1016/j.bmcl.2006.02.008

A series of N-alkyl-N-arylmethylpiperidin-4-amines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake.

Full text of DOI:10.1016/j.bmcl.2006.02.008

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2714–2718
N-Alkyl-N-arylmethylpiperidin-4-amines: Novel dual inhibitors
of serotonin and norepinephrine reuptake
J. R. Boot,a S. L. Boulet,b B. P. Clark,a M. J. Cases-Thomas,a L. Delhaye,c K. Diker,c
J. Fairhurst,a J. Findlay,a P. T. Gallagher,a,* J. Gilmore,a J. R. Harris,a J. J. Masters,b
S. N. Mitchell,a M. Naik,a R. G. Simmonds,a S. M. Smith,b S. J. Richards,a G. H. Timms,a
M. A. Whatton,a C. N. Wolfeb and V. A. Wooda
aEli Lilly and Company, Ltd, Lilly Research Centre, Windlesham, Surrey, GU20 6PH, UK
bLilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
cLilly Development Centre, Parc Scientifique de Louvain-la-Neuve, Rue Granbonpre´ 11, 1348 Mont-Saint-Guibert, Belgium
Received 30 November 2005; revised 3 February 2006; accepted 7 February 2006
Available online 23 February 2006
Abstract—A series of N-alkyl-N-arylmethylpiperidin-4-amines have been prepared and are demonstrated to be inhibitors of both
serotonin and norepinephrine reuptake.
Ó 2006 Elsevier Ltd. All rights reserved.
Major depressive disorder is currently the fourth leading
cause of disease or disability world wide and is projected
CF3
R1
to rise to second by 2020.1 Furthermore it has been sug-
gested that dual serotonin (5-HT) and norepinephrine
(NE) reuptake inhibitors offer the potential for superior
anti-depressant activity.2 That enhancing both seroto-
nergic and noradrenergic neurotransmission results in
anti-depressant efficacy is now supported by clinical
experience with duloxetine (CymbaltaTM) (1), a dual
5-HT and NE uptake inhibitor.3,4
N
O
NHMe
N
H
S
2
Duloxetine 1
Figure 1.
As part of a program seeking to identify new dual up-
take inhibitors a series of alkylaminopiperidines that
possess potent dual 5-HT and NE transport inhibition
properties have now been identified (Fig. 1).5,6
done (3) by reductive amination with either 2-trifluo-
romethylbenzylamine (4) or an alkylamine (7) to give
amines (5) and (8), respectively, in good yields (Scheme
1).7,8 Benzylamino piperidine (5) was reductively ami-
nated with either aldehyde or ketone (6). Conversely
alkylaminopiperidine (8) was reductively aminated with
either 2-trifluoromethylbenzaldehyde (9) or benzylated
with 2-trifluoromethylbenzyl bromide (10). Both routes
provided compounds (11–23) whose transporter affinity
is tabulated below (Table 1). Tartrate or fumarate salts
of the secondary amines were routinely prepared and
affinity data has been generated on these salts (Tables
1–4).
The initial compounds synthesized for this SAR were
analogues of 2 where R1 was varied to investigate which
alkyl, cycloalkyl and substituted alkyl groups main-
tained dual 5-HT and NE transport inhibition.
Alkylated 4-aminopiperidines were straightforwardly
synthesised by two general routes from N-Boc-piperi-
Keywords: Serotonin; Norepinephrine; Reuptake; Transporter; Inhib-
itors; Aminopiperidines.
Taking advantage of the availability of 4-bromobutyro-
nitrile and trifluoro-methanesulfonic acid 2-trifluoro-
methoxy-ethyl ester,9 benzylamino piperidine (5) was
*
Corresponding author. Tel.: +44 0 1276 483536; fax +44 0 1276
483525; e-mail: Gallagher_p@lilly.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.02.008

J. R. Boot et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2714–2718
2715
H, R
N
CF3
chain produces compounds with similar activity to the
un-fluorinated analogues. An exception to this latter
observation is the reduced activity of the trifluorometh-
oxy analogue (26) when compared to the methoxy ana-
logue (24).
CF3
H, R
Alkyl
NH2
CF3
O
N
Alkyl
b
HN
N
O
6
4
a
11-23
3
5
N
H
Boc
Boc
H, R
NH
H,R
NH2
Having investigated alkyl substituents it was decided to
retain a single alkyl chain and investigate the scope of
benzyl substitution.
CHO
CF3
CH2Br
CF3
Alkyl
Alkyl
7
9
10
a
b
N
Boc
The compounds in Table 2 were synthesized via N-Boc-
piperidine (8) (Scheme 1) and converted to compounds
28–43 by reductive amination with the requisite aryl
aldehyde.
8
Scheme 1. Reagents: (a) H2, EtOH, 10% Pd/C, 45–80%, (b) i—RCHO,
Na(AcO)3BH, DMF, ClCH2CH2Cl; ii—TFA, CH2Cl2; iii—tartaric
acid or fumaric acid MeOH, 15–75%.
Of the monosubstituted analogues synthesised (Table 2),
3- or 4-substitution (e.g., 29, 30, 32, 33, 35, 36) was det-
rimental to NE transporter affinity in comparison to 16.
However on replacing the trifluoromethyl with methyl
(34), chloro (40), methylthio (41) or trifluormethoxy
(42) groups, dual inhibition was retained.
alkylated under basic conditions to give the cyano and
trifluoromethoxy analogues (25 and 26) (Table 1). The
trifluoroethyl analogue was made by trifluoroacetylation
with trifluoroacetic anhydride, followed by reduction of
the trifluoroacetamide (28) with borane-THF to give
(27) (Scheme 2).
Affinity at the dopamine transporter was more prevalent
with certain substitution patterns, thus the 3-methyl
(35), 3-fluoro (38) and 2-chloro (40) substituents all
had inhibition of DA transport of less than 100 nM.
The compounds in Scheme 1 were evaluated for their
affinity at the 5-HT, NE and dopamine (DA) receptors.
neurotransmitter re-uptake (Table 1). Several com-
pounds with nanomolar affinity at SERT and NET were
identified. The following SAR conclusions can be
drawn: (i) that substitution on an alkyl chain alpha to
the 4-amine is detrimental to NE uptake (cf. 19), howev-
er cycloalkyl substitution, for example (20) does not im-
pact NE uptake; (ii) branching beta to the 4-amine has
less impact and is better tolerated (e.g., 16, 18 and 21);
(iii) substituting with fluorine at the terminus of an alkyl
Following the limited success of monosubstitution of the
aryl moiety a series of disubstituted analogues were syn-
thesized (Table 3). Disubstituted compounds were syn-
thesized analogously to the compounds in Table 2.
Disubstitution was more rewarding than monosubstitu-
tion. Thus maintaining methyl, trifluoromethyl or chlo-
ro substituents in the 2-position and substituting with
Table 1. Binding affinities at the serotonin, norepinephrine and dopamine transporters compounds 11–27.
CF3
R1
N
N
H
Compound
R1
Salta
5-HTb,c
NEb,c
DAb,c
(3 1%)
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Me–
Et–
A
A
A
A
A
A
A
A
A
A
A
A
A
B
(À40 7%)
(À67% 4%)c
8
0.2
61
2
(À2 0.2%)
(À12 1%)
(À31 3%)
(À31 2%)
210 30
n-Pr–
Me2CH–
n-Bu–
2.2 0.2
5.6 0.1
1.5 0.4
1.4 0.1
1.5 0.1
4.3 0.5
6.8 1.2
3.6 0.1
6.9 0.6
2.5 0.03
2.8 0.1
2.2 0.2
0.58 0.05
17 0.5
6.5 0.4
26
2
5.1 0.5
3.2 0.3
Me2CHCH2–
c-C3H5CH2–
Me3CCH2–
Et2CH–
6
1
(À27 0.1%)
160 14
2.7 0.1
86
2
(À41 0.4%)
(À45 0.7%)
(À39 1%)
(4 3%)
c-C5H9–
4.1 0.1
6.1 1.5
8.3 0.2
9.8 0.7
6.8 0.7
Et2CHCH2–
MeO(CH2)2–
F3C(CH2)2–
MeO(CH2)3–
NC(CH2)3–
F3CO(CH2)2–
F3CCH2–
(À35 3%)
(À8 2%)
(À15 1%)
(À8 1%)
(À22 2%)
B
21
51
33
2
1
2
B
B
4.6 0.4
a A, fumarate; B, tartrate.
b Ki, nM.
c % inhibition at 1 lM. Binding affinities and displacement measurements were done in triplicate.4

2716
J. R. Boot et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2714–2718
Table 2. Binding affinities at the serotonin, norepinephrine and dopamine transporters
N
R2
N
H
Compound
R2
Salta
5-HTb,c
1.4 0.1
NEb,c
DAb,c
200 30
16
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
2-CF3
H
A
3.1 0.3
91 6.4
255 13
FBd
A
8.4 0.6
0.26 0.02
0.07 0.01
1.2 0.04
0.48 0.07
0.28 0.01
1.5 0.4
(À60.4 0.8%)
(À63.9 0.6%)
(À28.5 2.2%)
(À10.3 1.6%)
201 32
3-CF3
4-CF3
2-CN
3-CN
4-CN
2-Me
3-Me
4-Me
2-F
A
300
42
7
2
A
A
690 22
190
A
2
(À24.2 0.6%)
240 19
98 2.9
A
3.3 0.2
150 21
A
2.2 0.1
FB
A
0.99 0.10
(À43.9 4.9%)
(À39 3.7%)
1.9 0.2
69
15 0.1
43
3
(À60.4 1.4%)
330 5.7
86.5 2.8
3-F
4-F
A
1
A
78 12
1.4 0.1
3.3 0.2
7.1 0.3
145 10
200 7.2
83
2-Cl
A
1.6 0.1
1.1 0.2
3
2-MeS
2-OCF3
2-MeO
A
(À17.5 0.1%)
(À16.4 0.3%)
(4.0 4.0%)
A
2.2 0.2
1
A
15
a A, fumarate; B, tartrate.
b Ki, nM.
c % inhibition at 1 lM. Binding affinities and displacement measurements were done in triplicate.4
d Free base.
Table 3. Binding affinities at the serotonin, norepinephrine and dopamine transporters
R2
R3
N
N
H
Compound
R2
R3
Salta
5-HTb,c
NEb,c
DAb,c
16
44
45
46
47
48
49
50
51
52
53
54
55
2-CF3
2-CF3
2-MeO
2-F
H
5-F
A
A
A
A
A
A
A
A
A
A
A
A
A
1.4 0.1
7.9 0.9
2.2 0.2
3.2 0.3
210 30
(À19 2%)
(1.8 1.6%)
580 40
3.4 0.1
1060 30
20 2.3
4-MeO
4-F
3.1 0.40
0.39 0.12
4.1 0.40
1.4 0.14
0.30 0.1
0.96 0.1
0.48 0.1
2.1 0.2
2-Me
2-CF3
2-MeO
2-CF3
2-Cl
4-Me
6-F
5-F
4.8 0.3
6.0 0.8
(À16 1%)
(À18 2%)
(À2 1.8%)
190 20
42.1
2
4-F
1.8 0.3
2.0 0.2
420 18
5.5 0.30
4-Cl
3-CF3
5-Cl
5-CF3
4-CF3
230 20
2-Cl
2-Cl
(À37 3%)
(À22 3%)
(À11 3%)
120 20
2-Cl
2-F
9.6
5.8
1
1
175 9
2.2 0.1
a A, fumarate; B, tartrate.
b Ki, nM.
c % inhibition at 1 lM. Binding affinities and displacement measurements were done in triplicate.4
fluorine, methyl or chlorine produced potent dual inhib-
itors (e.g., 47, 50). Notable exceptions are the 2,4-dime-
thoxy analogue (45) which retained SERT affinity (Ki vs
SERT = 2.2 nm) but had much reduced NET affinity (Ki
vs NET > 1 lM) and the trifluoromethyl analogues (52
and 54) which also had reduced NET affinity of
Ki = 419 nm and 175 nm, respectively.
dual SERT and NET inhibition and tolerance to alkyl
chain modification was reinvestigated.
Alkyl and alkoxy alkyl analogues (65–72) were synthe-
sized by reductive amination with N-Boc protected ben-
zylamine (60) with selected carboxaldehydes followed by
deprotection.
From this exercise the 4-fluoro-2-trifluoromethyl substi-
tution pattern was selected for optimization towards
Additional nitrile analogues (Scheme 3) were synthe-
sized to improve upon the NET affinity of 25. The

J. R. Boot et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2714–2718
Table 4. Binding affinities at the serotonin, norepinephrine and dopamine transporters
2717
CF3
R1
N
F
N
H
Compound
R1
Salta
5-HTb,c
NEb,c
1.8 0.3
DAb,c
50
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
Me2CHCH2–
n-Pr–
n-Bu–
A
A
A
A
B
B
B
B
B
B
B
B
B
A
B
B
0.3 0.1
0.8 0.2
1.3 0.1
0.8 0.1
0.4 0.05
2.5 0.7
1.1 0.3
2.8 0.1
3.0 0.6
0.4 0.05
0.4 0.05
4.2 0.3
0.7 0.05
3.1 0.2
4.0 0.5
5.0 0.3
200 20
3.6 0.5
8.3 1.4
6.1 0.5
6.5 0.7
3.1 0.5
5.4 0.8
9.6 1.0
9.7 0.6
13.3 1.5
13.3 1.5
15.9 1.2
6.2 0.4
95.9 6.3
4.2 0.3
(À23 1.3%)
(À21 3%)
(À32 2%)
(À26 2%)
(À22 2%)
(À45 2%)
(À7 0.2%)
(À3 0.1%)
(5 0.5%)
c-C3H5CH2–
c-C3H5CH2–
c-C4H7CH2–
MeO(CH2)3–
EtO(CH2)2–
Me2CHO(CH2)2–
NC(CH2)2–
(À4 0.5%)
(10 1.2%)
(À17 0.6%)
(À23 2%)
(À7 1%)
NC(CH2)3–
Me2(CN)CCH2–
Me2(CN)C(CH2)2–
HO(CH2)2–
Me2(OH)CCH2–
Me2(OH)C(CH2)2–
(À8 1%)
(1.3 0.9%)
a A, fumarate; B, tartrate.
b Ki, nM.
c % inhibition at 1 lM. Binding affinities and displacement measurements were done in triplicate.4
CF3
CF3
CF3
CF3
OHC
a
NC
N
CN
NH
NH
O
NC
NC
N
NH2
58
56
F
5
25
F
b
N
H
N
Boc
a
N
Boc
57
b
N
Boc
3
c
N
H
73
CF3
O
CF3
OCF3
CF3
N
F3C
N
N
CF3
NC
c
NC
N
N
N
N
H
28
26
F
F
Boc
N
59
75
d
Boc
H
CF3
CF3
CF3
CHO
F3C
N
NC
HN
61
NC
N
27
F
F
N
H
d
N
Boc
N
H
60
76
Scheme 2. Reagents: (a)—i Br(CH2)3CN, K2CO3, CH3CN, 45%; ii—
TFA, CH2Cl2, 87%, (b) i—CF3O(CH2)2OSO2CF3, K2CO3, CH3CN
63%; ii—TFA, CH2Cl2 96%; iii—tartaric acid, MeOH, 87%, (c) i—
(CF3CO)2O, DMAP, Et3N, CH2Cl2, 81%, (d) i—BH3, THF, 70%; ii—
TFA, CH2Cl2, tartaric acid, MeOH, 39%.
Scheme 3. Reagents: (a) i—56, Na(OAc)3BH, THF, 70%, (b) 58,
Na(OAc)3BH, THF; iii–TFA, CH2Cl2; iv—tartaric acid, MeOH, 38%
for steps ii–iv, (c) i—LDA, MeI, THF, 32%; ii—TFA, CH2Cl2; iii—
tartaric acid MeOH, 20% for steps ii–iii, (d) i—61, Na(OAc)3BH,
THF, 97%; ii—TFA, CH2Cl2; iii—tartaric acid MeOH, 66% for steps
ii–iii.
cyanoethyl analogue (73) was synthesized from N-Boc-
piperidone (3) by consecutive reductive aminations
with aminopropionitrile (56) to give protected
hydroxyethylamino piperidine (57) and then 4-fluoro-
2-trifluoromethylbenzaldehyde (58) and subsequent
deprotection.
The higher homologue of (75) was obtained via reduc-
tive amination with 2,2-dimethyl-4-oxobutyronitrile10
(61) followed by deprotection to give (76) (Scheme 3).
Seeking groups with comparable hydrogen bond accept-
ing capability to the nitrile function, prompted the syn-
thesis of (77–79) (Scheme 4).11 These were synthesized
according to Scheme 4. Thus N-Boc piperidone (3) was
Di-alkylation alpha to the nitrile group of (59) with
LDA and methyl iodide, followed by deprotection with
trifluoroacetic acid produced (75).

2718
J. R. Boot et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2714–2718
CF3
As no improvement in NET transporter activity over
CF3
OHC
HO
(16) was observed on varying the side chain of the 4-flu-
oro-2-trifluoromethylbenzyl analogues it was decided to
advance (16) into in vivo studies. Thus in in vivo micro-
dialysis experiments with (16), increases above basal lev-
els of synaptic 5-HT and NE levels of 202 24% and of
249 21%, respectively, at 3 mg/kg po have been dem-
onstrated. Further in vivo studies will be published
elsewhere.
HO
O
NH
N
HO
NH2
F
58
62
F
b
a
N
Boc
N
Boc
77
N
H
63
3
CF3
HO
63
O
N
CF3
F
c
78
HN
N
N
H
d
References and notes
F
CF3
O
HO
N
1. Murray, C. J. L.; Lopez, A. D., Eds.; The Global Burden of
Disease: A Comprehensive Assessment of Mortality an
Disability from Diseases, Injuries and Risk Factors in 1990
and Projected to 2020. Cambridge Mass: Harvard Univer-
sity Press, 1996.
60
Boc
64
F
79
N
H
Scheme 4. Reagents: (a) i—62, Na(OAc)3BH, THF, 70%, (b) 58,
Na(OAc)3BH, THF; iii—TFA, CH2Cl2; iv—fumaric acid, MeOH,
38% for steps ii–iv, (c) i—63, LiClO4, MeOH, 65 °C, 71%; ii—TFA,
anisole, CH2Cl2, 92%; iii—tartaric acid, MeOH, 99%, (d) i—64,
CHCl3, 99%; ii—MeMgCl, THF, 92%; iii—TFA, CH2Cl2; iv—tartaric
acid, MeOH, 58% for steps iii–iv.
2. Wong, D. T.; Bymaster, F. P. Prog. Drug Res. 2002, 58,
169.
3. Detke, M. J.; Lu, Y.; Goldstein, D. J.; Hayes, J. R.;
Demitrack, M. A. J. Clin. Psychiatry 2002, 63, 308.
4. The ligands for determining the Ki values at the NE, 5-HT
and dopamine transporters were [3H]nisoxetine, [3H]ci-
talopram and [3H]WIN35,428, respectively. Bymaster, F.
P.; Beedle, E. E.; Findlay, J.; Gallagher, P. T.; Krushinski,
J. H.; Mitchell, S.; Robertson, D. W.; Thompson, D. C.;
Wallace, L.; Wong, D. T. Bioorg. Med. Chem. Lett. 2003,
13, 4477.
5. Boot, J. R.; Brace, G.; Delatour, C. L.; Dezutter, N.;
Fairhurst, J.; Findlay, J.; Gallagher, P. T.; Hoes, I.;
Mahadevan, S.; Mitchell, S. N.; Rathmell, R. E.;
Richards, S. J.; Simmonds, R. G.; Wallace, L.;
Whatton, M. A. Bioorg. Med. Chem. Lett. 2004, 14,
5395.
reductively aminated with ethanolamine (62) to give 63,
followed by reductive amination with aldehyde 58 and
deprotection to give alcohol 77. Benzylamino piperidine
60 was alkylated with epoxide 63 to give a tertiary alco-
hol (78). The higher homologue of 78 was prepared by
conjugate addition to ketone 64 followed by Grignard
reaction with methyl magnesium chloride to give (79).
Maintaining the aryl substitution as 4-fluoro-2-trifluoro-
methyl showed that of the alkyl chains examined the
activity paralleled that of the analogues in Table 1. Im-
proved NET inhibition was not observed with the ana-
logues in Table 4, however the compound having the
closest affinity to the isobutyl side chain was the cyclo-
butylmethyl analogue (69). However (69) had weaker
SERT inhibition than (16).
6. Boot, J. R.; Cases, M.; Clark, B. P.; Findlay, J.; Gallagher,
P. T.; Hayhurst, L.; Man, T.; Montalbetti, C.; Rathmell,
R. E.; Rudyk, H.; Walter, M. W.; Whatton, M.; Wood, V.
Bioorg. Med. Chem. Lett. 2005, 15, 699.
7. Finke, P. E.; Oates, B.; Mills, S. G.; MacCoss, M.;
Malkowitz, L.; Springer, M. S.; Gould, S. L.; DeMartino,
J. A.; Carella, A.; Carver, G.; Holmes, K.; Danzeisen, R.;
Hazuda, D.; Kessler, J.; Lineberger, J.; Miller, M.; Schleif,
W. A.; Emini, E. A. Bioorg. Med. Chem. Lett. 2001, 11,
2475.
8. Clark, B. P.; Cases-Thomas, M. J.; Gallagher, P. T.;
Gilmore, J.; Masters, J. J.; Timms, G. T.; Whatton, M. A.;
Wood, V. A. WO 2004, 052858.
9. Blazejewski, J. C.; Anselmi, E.; Wakselman, C. J. Org.
Chem. 2001, 66, 1061.
Of the nitrile analogues synthesized, three showed
sub-nanomolar affinity at the 5-HT transporter and
one of these (76), had the highest NET affinity (Ki vs
NET = 6.2 nm) of any nitrile investigated.
The decision to replace the nitrile functionality with an
alcohol moiety was also rewarded with good dual activ-
ity with (78), however the hydroxyethyl (77) analogue
was one of the least active analogues in this SAR.
10. Des Abbayes, H. Bulletin de la Societe Chimique de France
1970, 10, 3661.
11. Abraham, M. H.; Platts, J. A. J. Org. Chem. 2001, 66,
3484.