4-Piperidines and 3-pyrrolidines as dual serotonin and noradrenaline reuptake inhibitors: Design, synthesis and structure-activity relationships

Article abstract of DOI:10.1016/j.bmcl.2009.03.090

Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5-9 are inhibitors of monoamine reuptake. Structure-activity relationships established that monoamine reuptake inhibition are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Consequently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l-a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative examples from this series.

Full text of DOI:10.1016/j.bmcl.2009.03.090

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2829–2834
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
4-Piperidines and 3-pyrrolidines as dual serotonin and noradrenaline
reuptake inhibitors: Design, synthesis and structure–activity relationships
*
Paul V. Fish , Mark D. Andrews, M. Jonathan Fray, Alan Stobie, Florian Wakenhut, Gavin A. Whitlock
Discovery Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Single enantiomer [(aryloxy)(pyridinyl)methyl]piperidine and pyrrolidine derivatives 5–9 are inhibitors
of monoamine reuptake. Structure–activity relationships established that monoamine reuptake inhibi-
tion are functions of amine, pyridine isomer, aryloxy ring substitution and stereochemistry. Conse-
quently, selective NRIs, selective SRIs, dual SNRIs and triple SNDRIs were all identified. Dual SNRIs 5l–
a and 9c were evaluated in additional pharmacology and pharmacokinetic studies as representative
examples from this series.
Received 5 March 2009
Revised 16 March 2009
Accepted 21 March 2009
Available online 26 March 2009
Keywords:
Dual SNRI
Ó 2009 Elsevier Ltd. All rights reserved.
Selective SRI
Selective NRI
Triple SNDRI
4-Piperidine
3-Piperidine
3-Pyrrolidine
Monoamine reuptake inhibitor
Dual serotonin (5-HT) and noradrenaline (NA) reuptake inhibi-
tors (SNRI) have proven to be an effective treatment for a number
of indications including depression, anxiety disorders, fibromyal-
gia, painful peripheral neuropathy and stress urinary inconti-
nence.1,2 The search for potent and selective SNRIs has identified
venlafaxine (1),3 duloxetine (2)4 and milnacipran (3)5 which are
all marketed drugs. Furthermore, several small molecule SNRIs
have been reported to be in early clinical development or undergo-
ing preclinical optimization and evaluation.6 Hence, the discovery
of new SNRIs with enhanced properties continues to be an attrac-
tive target for the pharmaceutical industry.
We have reported several new templates that inhibit mono-
amine reuptake and some of these compounds have now pro-
gressed to clinical trials.7 As part of our research efforts to
identify potential new SNRI drug candidates, we adopted a strategy
of exploring multiple chemical templates in order to increase our
chances of having compounds survive to become advanced clinical
candidates.
In this Letter, we disclose derivatives of 4-[(aryloxy)(pyridi-
nyl)methyl]piperidines
(5–7)
and
3-[(aryloxy)(pyridi-
nyl)methyl]pyrrolidines (9) as potent dual SNRIs with selectivity
over dopamine (DA) reuptake inhibition (DRI). In addition, we dis-
cuss some factors that modulate SRI–NRI–DRI activity and present
additional pharmacology and pharmacokinetic data on representa-
tive examples from this series.
MeO
NHMe
S
Investigation of the 3-(aryloxy)-3-phenylpropanamine tem-
plate has identified a number of monoamine reuptake inhibitors
including fluoxetine, nisoxetine, atomoxetine and duloxetine (2)
(Fig. 1).8 Modification of this template by cyclization into a piper-
idine ring to furnish 4-[(aryloxy)(phenyl)methyl]piperidines 4 has
been reported by Orjales et al. (e.g., 10).9 Our own limited explora-
tion of this template furnished potent dual SNRI 11 (Table 1). How-
ever, 11 had some degree of liver microsomal instability and
carried ion channel activity; these properties could be attributed
to the highly lipophilic nature of this amine template (clogP 5;
cpKa 10).
NH2
O
NMe2
OH
Et
O
N
Et
1: venlafaxine
2: duloxetine
3: milnacipran
We proposed that a new SNRI template would benefit from a
significant decrease in lipophilicity as this was likely to improve
* Corresponding author. Tel.: +44 (0) 1304 644589; fax: +44 (0) 1304 651987.
E-mail address: paul.fish@pfizer.com (P.V. Fish).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.090

2830
P. V. Fish et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2829–2834
create ring
ring (i.e., 4?5–9) as this would significantly reduce lipophilicity
compared to 4 (
D
clogP À1.5 to À2.0) whilst retaining a pharmaco-
phore with potential for inhibition of monoamine reuptake (Fig. 1).
Hence, a detailed investigation of the structure–activity relation-
ships (SAR) of the 4-piperidines 5–7, 3-piperidines 8 and 3-pyrrol-
idines 9 was undertaken with the primary objective of optimizing
dual SNRI activity in these more polar templates.
Me
NH
introduce polar
heterocycles
e.g. Py
O
tune activity &
physicochemical
properties
R
4-Piperidines 5–7 (Table 2) were conveniently prepared in a
three-step sequence as described in Scheme 1. Bromopyridines
12a–c were converted to the corresponding Grignard reagents
and then reaction with aldehyde 13 gave racemic alcohols 14.
Treatment of 14 with phenols ArOH under Mitsunobu conditions
gave aryloxy ethers 15 and deprotection of the N-Boc amine with
TFA afforded the target compounds 5–7. The two pairs of single
enantiomers of 5l–a/b and 5m–a/b (Table 3) were prepared by sep-
aration of the corresponding racemic N-Boc aryloxy ethers 15 by
chiral HPLC followed by deprotection with TFA.
3-(Aryloxy)-3-phenylpropanamines
fluoxetine (R = 4-CF3)
nisoxetine (R = 2-OMe)
atomoxetine (R = 2-Me)
4
3
m( )
The synthesis of (3R)-piperidines 8a,b (Table 4) is illustrated in
Scheme 2. Resolution of ( )-ethyl nipecotate (16) with L-(+)-tar-
NH
( )n
NH
R1
N
2
taric acid by the method of Gollamudi12 gave (R)-17 (>99% ee)
and (S)-18 (>99% ee). 3-Piperidine 17 was then protected as the
N-Boc amine 19. Reduction of 19 with DIBAL gave alcohol 20 and
oxidation under Swern conditions gave aldehyde 21 which was
converted through to (3R)-piperidines 8a,b by the three-step se-
quence as described for 4-piperidines in Scheme 1. The (3S)-piper-
idines 8c,d were prepared by an identical sequence but starting
with (S)-ethyl nipecotate 18.
O
O
R2
R2
4
5: 4-piperidines (m = 1; n = 1; 3-pyridine)
6: 4-piperidines (m =1; n =1; 2-pyridine)
7: 4-piperidines (m = 1; n = 1; 4-pyridine)
8: 3-piperidines (m = 2; n = 0; 3-pyridine)
9: 3-pyrrolidines (m = 1; n = 0; 2-pyridine)
The synthesis of (3R)-pyrrolidines 9a,b (Table 4) is shown in
Scheme 3. The chiral (3R)- and (3S)-pyrrolidine rings were con-
structed by Michael addition and cyclization of (R)-a-methylben-
Figure 1. Design of 4-piperidines 5–7, 3-piperidines 8 and 3-pyrrolidines 9 derived
from 3-(aryloxy)-3-phenylpropanamines.
zylamine (23) with dimethyl itaconate (22) to give an equal
mixture of lactams 24 and 25 as described by Domagala;13 this
mixture of lactams was separated by chromatography to give
(R,R)-24 (>99% de) and (R,S)-25 (>99% de). Reduction of 24 with
LiAlH4 gave alcohol 26 and the N-benzyl chiral auxiliary/protecting
group was exchanged for the N-Boc amine 27 by transfer hydroge-
nation in the presence of (Boc)2O. Oxidation of 27 under Swern
conditions gave aldehyde 28 which was converted through to
(3R)-pyrrolidines 9a,b by the three-step sequence as described
for 4-piperidines in Scheme 1. The (3S)-pyrrolidines 9c,d were pre-
pared by an identical sequence but starting with (R,S)-lactam 25.
Target compounds 5–9, 10 and 11 (Tables 1–4) were tested for
their ability to inhibit the uptake of [3H]-5-HT, [3H]-NA and [3H]-
DA in HEK293 cells expressing a single human transporter.14 Com-
pound lipophilicity was assessed by calculation of partition coeffi-
cients (clogP). Selected compounds were then screened for
metabolic stability in human liver microsomes (HLM), for CYP2D6
inhibition, and binding to the potassium hERG channel as a mea-
sure of ion channel activity.
Table 1
Physicochemical properties, in vitro inhibition of monoamine reuptake, and ion
channel affinities of racemic 10 and 11a,b,c
NH
NH
O
O
Cl
Cl
10
11
10d
11e
M.wt.
317
5.0
21
336
5.1
21
8
16
200
87
950
840
clogP
TPSA (Å2)
5-HT, IC50 (nM)
NA, IC50 (nM)
DA, IC50 (nM)
HLM, T1/2 (min)
K+ hERG, IC50 (nM)
Na+ TTX-S, IC50 (nM)
15
120
370
NT
NT
NT
The SAR of the aryloxy ring (R2) was initially explored in the 3-
Py isomer 5. Introduction of lipophilic groups at the 2-position
(5a–e) gave SNRIs with the 2-Cl 5a having the most potent dual
activity. Appropriate monosubstitution also gave selective NRIs
and selective SRIs: 5f (R2 = 2-Ph) was a very potent NRI with good
selectivity over SRI and DRI activity (>50-fold); 5j (R2 = 4-Et) and
5k (R2 = 4-SMe) were potent SRIs with excellent selectivity over
both NRI and DRI (>600-fold). The combination of 2- and 3-disub-
stitution gave potent dual SNRIs 5l, 5n, 5o and the introduction of a
6-Me group onto the Py ring, compound 5m, was tolerated and
marginally reduced DRI activity (5l vs 5m). The corresponding
2,4-dichloro analogue 5p was a selective SRI and so NRI activity
had been lost by inclusion of a 4-Cl group (5p vs 5a).
a
See Ref. 14 for details of assay conditions and Ref. 16 for definition of terms.
Monoamine reuptake IC50 values are geometric means of at least two experi-
b
ments. Differences of <2-fold should not be considered significant.
c
NT denotes not tested.
Compound 10 was first disclosed by Orjales et al., see: Ref. 9. Data is presented
d
for comparison in a common assay format.
e
Compound 11 is novel. This work.
metabolic stability, decrease ion channel activity and reduce the
risk of potential toxicological outcomes;10 this reduction in lipo-
philicity would need to be balanced with retaining good central
nervous system (CNS) permeability.11 A suitable modification of
this template would be exchanging the phenyl ring for a pyridine
The SAR of the 2-Py isomer 6 generally mimicked that of 5 as an
NRI 6a was again achieved with bulky R2 = 2-Ph, and 6b (R2 = 2-Cl;
3-Cl) was a potent dual SNRI. The 2-Py template was also used to
further explore the SAR of methyl substitution (R1 = Me). The 2-

P. V. Fish et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2829–2834
2831
Table 2
In vitro inhibition of monoamine reuptake for racemic 4-piperidines 5, 6 and 7a,b,c
NH
NH
N
NH
R1
R1
R1
N
N
O
O
O
R2
R2
R2
5: 3-Py
6: 2-Py
7: 4-Py
Compound
R1
R2
clogP
5-HT
NA
DA
IC50 (nM)
IC50 (nM)
IC50 (nM)
Duloxetine (2)d
—
H
H
H
H
H
H
H
H
H
H
H
H
6-Me
H
H
H
H
H
H
H
H
—
2-Cl
2-Et
2-OEt
2-CF3
2-OCF3
2-Ph
2-OPh
3-Cl
4.3
3.0
3.4
2.6
3.5
3.2
3.7
4.1
3.2
3.4
3.4
2.9
3.6
4.1
2.6
3.3
3.7
3.7
4.0
4.3
3.7
3.6
4.1
4.1
4.1
3.7
3.6
3.7
4
9
5
30
91
13
106
45
2
23
23
404
4850
5850
7
14
24
42
>400
84
>400
215
33
590
400
5a
5b
5c
5d
5e
5f
5g
5h
5i
61
80
77
95
109
76
3
7
5
7
11
14
3
3
5
>4000
>2920
ND
>40,000
>40,000
>4000
1600
ND
3-Et
4-Et
4-SMe
5j
5k
5l
7830
>30,000
150
2-Cl; 3-Cl
2-Cl; 3-Cl
2-F; 3-F
2-Me; 3-Me
2-Cl; 4-Cl
2-Cl; 5-Cl
3-Cl; 5-Cl
2-Cl; 3-Cl; 5-Cl
2-Ph
2-Cl; 3-Cl
2-Cl; 3-Cl
2-Cl; 3-Cl
2-Cl; 3-Cl
2-Cl; 4-Cl
2-Cl; 3-Cl
2-Cl; 4-Cl
5m
5n
5o
5p
5q
5r
5s
6a
6b
6c
6d
6e
6f
590
1070
1270
480
>4000
ND
ND
ND
353
ND
644
3470
ND
60
ND
7
10
10
>400
6
11
8
16
7
8
23
>400
35
48
>400
8
3-Me
4-Me
5-Me
H
H
H
7a
7b
7
>400
a
See Ref. 14 for complete details of assay conditions.
Monoamine reuptake IC50 values are geometric means of at least two experiments. Differences of <2-fold should not be considered significant.
ND denotes not determined.
b
c
d
Data is presented for comparison in a common assay format.
Py ring could accommodate a Me group at the 4- and 5-positions to
give SNRIs (6b vs 6d, 6e) although the 3-Me isomer 6c retained SRI
activity but NRI activity was lost. The 4-Py 7a also gave dual SNRI
activity but with the most significant DRI activity of the three pyr-
idine isomers (5l vs 6b vs 7a).
Boc
N
R1
R1
Boc
N
a
N
N
+
Br
OH
CHO
In summary, an emerging understanding of the SAR within
these 4-piperidine scaffolds 5–7 showed that the aryloxy ring
played an important role in modulating NRI and SRI activity; that
is, appropriate substitution at the 2-position conferred capricious
NRI activity whereas substitution at the 3/4-position gave robust
SRI activity. The NRI activity was sensitive to both the position
and the nature of the R2 group whereas SRI activity was less sensi-
tive to these factors and more tolerant of groups at other positions
on the ring. From this analysis, 5l and 5m emerged as examples
with a combination of superior dual SNRI activity and selectivity
over DRI.
Caution must be exercised when evaluating SAR from the bio-
logical activities of racemic compounds as the contribution to the
observed effects may not be equal for each enantiomer; this is
further complicated when seeking dual activities at two biological
targets.15 Hence, compound 5l and 5m were then prepared as the
two single enantiomers 5l–a,b and 5m–a,b so as to determine the
influence of absolute stereochemistry on SRI, NRI and DRI activity
(Table 3).
12a: 3-Py (shown)
12b: 2-Py
12c: 4-Py
13
14
b
R1
R1
Boc
N
NH
c
N
N
O
O
R2
R2
15
5: 3-Py (shown)
6: 2-Py
7: 4-Py
Scheme 1. General synthesis of 4-piperidines 5–7. Reagents and conditions: (a) i-
PrMgCl, THF, 0 °C?rt; (b) ArOH, Me2NCON@NCONMe2, n-Bu3P, toluene, 85 °C; (c)
TFA, CH2Cl2, rt.

2832
P. V. Fish et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2829–2834
Table 3
In vitro inhibition of monoamine reuptake,a,b human liver microsomal stability,c CYP2D6 inhibition and hERG binding activity for single enantiomer 4-piperidines 5d
R1
NH
N
*
O
Cl
Cl
5
Compound
R1
stereochemistryd
*
5-HT
IC50 (nM)
NA
IC50 (nM)
DA
IC50 (nM)
HLM
T1/2 (min)
CYP2D6-i
IC50 (nM)
K+, hERG
IC50 (nM)
Duloxetinee
5l-a
5l-b
5m-a
5m-b
—
H
H
Me
Me
—
4
7
3
16
37
5
6
128
17
220
590
71
375
270
820
>120
>120
>120
>120
>120
1,000
20,000
2000
30,000
5500
Enantiomer 1
Enantiomer 2
Enantiomer 1
Enantiomer 2
5180
1970
a
See Ref. 14 for details of assay conditions.
Monoamine reuptake IC50 values are geometric means of at least two experiments. Differences of <2-fold should not be considered significant.
Maximum measurable half-life was 120 min.
Compounds are single enantiomers of undetermined absolute stereochemistry.
Data is presented for comparison in a common assay format.
b
c
d
e
Screening of the separate enantiomers showed one isomer
Additional pharmacokinetic data for 5l–a was generated in vitro
and in vivo in rat (Table 5). Screening in rat liver microsomes
showed 5l–a to have low metabolic stability (RLM, T1/2 5 min) con-
sistent with high predicted clearance. Following single intravenous
administration in rat, plasma clearance of 5l–a was high relative to
liver blood flow resulting in an elimination half-life of 2.0 h. Com-
pound 5l–a distributes extensively into tissues as shown by the
high volume of distribution. Furthermore, it was encouraging that
5l–a had physicochemical properties predicted to be consistent
with CNS target space.11,16,17
The next phase of analogue design was to investigate 3-piperi-
dines 8 and 3-pyrrolidines 9 where the relative positions of the
amine N-atom and the distal aromatic groups could more closely
mimic the spatial arrangement of duloxetine (2). 3-Piperidines 8
had significant activity at all three transporters with isomer 8a
possessed more SRI, NRI and DRI activity combined with weaker
activity for CYP2D6 and hERG inhibition (Table 3). Compounds
5l–a and 5m–a were potent dual SNRIs with selectivity over
DRI (10- and 15-fold, respectively), excellent metabolic stability
consistent with low predicted clearance, and minimal CYP2D6
inhibition.
Compound 5l–a was then evaluated in additional pharmacology
and pharmacokinetic screens as a representative example from
this series. Compound 5l–a had reduced ion channel activity com-
pared to 11 as measured by binding to sodium (TTX-S: IC50
2530 nM) and potassium (hERG: IC50 5180 nM) channels, and min-
imal off-target activity against a panel of representative aminergic
receptors (5-HT1A, 5-HT3,
200 nM).
a2, H3: <15% @ 200 nM; 5-HT2A: 30% @
Table 4
In vitro inhibition of monoamine reuptake,a,b human liver microsomal stability,c CYP2D6 inhibition and hERG binding activity for single enantiomer 3-piperidines 8 and 3-
pyrrolidines 9d
NH
N
NH
N
*
*
#
O
#
O
Cl
Cl
Cl
Cl
8
9
Compound
Stereochemistryd
#
5-HT
NA
DA
HLM
CYP2D6-i
IC50 (nM)
2400
K+, hERG
IC50 (nM)
6610
*
IC50 (nM)
IC50 (nM)
IC50 (nM)
T1/2 (min)
8a
8b
8c
8d
9a
9b
9c
9d
R
R
S
S
R
R
S
S
Enantiomer 1
4
9
35
3
13
44
9
14
43
6
99
53
36
720
330
1060
1530
Enantiomer 2
Enantiomer 1
Enantiomer 2
Enantiomer 1
Enantiomer 2
Enantiomer 1
Enantiomer 2
16
54
3
18
17
36
13
>120
>120
5300
600
10,000
>10,000
a
See Ref. 14 for details of assay conditions.
Monoamine reuptake IC50 values are geometric means of at least two experiments. Differences of <2-fold should not be considered significant.
Maximum measurable half-life was 120 min.
b
c
d
Compounds are single enantiomers with one chiral center of undetermined absolute stereochemistry.

P. V. Fish et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2829–2834
Table 5
2833
CO2Et
CO2Et
CO2Et
Pharmacokinetic parameters of 5l–a after single intravenous administration to rat
R
S
a
+
N
H
N
H
N
H
Rat (n = 2)
Intravenous dose (mg/kg)
5
Elimination half-life, T1/2 (h)
Plasma clearance, Cl (ml/min/kg)
Volume of distribution, Vd (l/kg)
2.0
180
33
17.(+)-L-tartrate
16
18.(+)-L-tartrate
b
being a potent triple SNDRI (Table 4).18 3-Pyrrolidines 9 proved to
be some of the most potent and selective dual SNRIs identified in
this work (Table 4). Both compounds 9c and 9d had good selectiv-
ity over DRI (>30-fold), excellent HLM stability and weak hERG
activity, however 9c offered an advantage of weaker CYP2D6
inhibition.
Cerebrospinal fluid (CSF) concentrations were then used as a
surrogate measure of CNS availability for 9c.19 Administration of
9c17 (3.1 mg/kg iv bolus, followed by 2.0 mg/kg iv infusion over
60 min, n = 2) showed a CSF-free plasma ratio of 0.36 0.05
(mean sem) confirming reasonable CNS exposure.20
CO2Et
R
OH
R
c
N
N
Boc
Boc
19
20
d
In conclusion, we have designed and evaluated a new series of
4-piperidine 5–7, 3-piperidine 8 and 3-pyrrolidine 9 derivatives
as inhibitors of monoamine reuptake. Structure–activity relation-
ships established that monoamine reuptake inhibition are func-
tions of amine, pyridine isomer, aryloxy ring substitution and
stereochemistry. Consequently, selective NRIs (5f), selective SRIs
(5k), dual SNRIs (5l–a, 5m–a, 9c) and triple SNDRIs (8a) were all
identified. Furthermore, selected examples had excellent HLM sta-
bility, weak CYP2D6 inhibition, modest ion channel activity, and
reasonable CNS penetration. The next phase of evolution of these
templates will be reported in future publications.
CHO
N
NH
R
R
as above
O
N
Boc
Cl
21
Cl
8a: enantiomer 1
8b: enantiomer 2
Scheme 2. Synthesis of (3R)-piperidines 8a,b. Reagents and conditions: (a) L-(+)-
tartaric acid, EtOH; (b) (Boc)2O, NaHCO3, CH2Cl2, rt, 24 h; (c) DIBAL, CH2Cl2, 0 °C?rt,
18 h; (d) (COCl)2, Me2SO, EtN(iPr)2, À78 °C.
CO2Me
Acknowledgements
CO2Me
Ph
R
S
CO2Me
MeO2C
a, b
We thank Carol Bains, Alan Jessiman, Arnaud Lemaitre, Debbie
Lovering, Malcolm Mackenny and Usa Reilly for compound synthe-
sis. We are grateful to Stephen Phillips (Discovery Biology), Ian
Gurrell (PDM), Anthony Harrison (PDM) and Nicola Lindsay
(PDM) for screening data. We acknowledge the excellent support
of the Structural and Separation Sciences group and would also like
to thank Katherine England and Gerwyn Bish for their assistance in
the preparation of this manuscript.
O
N
R
O
N
R
+
Me
Ph
Me
22
24
25
c
References and notes
OH
OH
R
R
1. (a) Montgomery, S. Int. J. Psych. Clin. Pract. 2006, 10, 5; (b) Baldwin, D. S. Int. J.
Psych. Clin. Pract. 2006, 10, 12; (c) Ueceyler, N.; Haeuser, W.; Sommer, C.
Arthritis Rheumatism 2008, 58, 1279; (d) Wernicke, J. F.; Iyengar, S.; Ferrer-
Garcia, M. D. Curr. Drug Therapy 2007, 2, 161; (e) Mariappan, P.; Alhasso, A.;
Ballantyne, Z.; Grant, A.; N’Dow, J. Eur. Urology 2007, 51, 67.
d
N
N
R
Boc
Me
Ph
2. For a recent review, see: Whitlock, G. A.; Andrews, M. D.; Brown, A. D.; Fish, P.
V.; Stobie, A.; Wakenhut, F. Top. Med. Chem. Published on-line 11th December,
2008. doi:10.1007/7355_2008_028.
27
26
3. Cheng, X.-M. Ann. Rep. Med. Chem. 1995, 30, 295.
4. Hedge, S.; Schmidt, M. Ann. Rep. Med. Chem. 2005, 40, 443.
5. Galaatsis, P. Ann. Rep. Med. Chem. 1998, 33, 338.
e
6. For recent reviews of new SNRI chemical entities, see: (a) Walter, M. W. Drug
Dev. Res. 2005, 65, 97; (b) Huang, Y.; Williams, W. A. Expert Opin. Ther. Patents
2007, 17, 889.
NH
CHO
R
N
R
7. Fish, P. V.; Barta, N. S.; Gray, D. L. F.; Ryckmans, T.; Stobie, A.; Wakenhut, F.;
Whitlock, G. A. Bioorg. Med. Chem. Lett. 2008, 18, 4355. and references cited
therein.
as above
O
N
Boc
8. Baldessarini, R. J. In Goodmans and Gilman’s The Pharmacological Basis of
Therapeutics, 11th ed.; Brunton, L. L.; Lazo, J. S.; Parker, K. L., Eds.; McGraw-Hill:
New York, 2005; Chapter 17, p 429.
9. Orjales, A.; Mosquera, R.; Toledo, A.; Pumar, M. C.; Gracia, N.; Cortizo, L.;
Labeaga, L.; Innerarity, A. J. Med. Chem. 2003, 46, 5512.
Cl
Cl
9a: enantiomer 1
9b: enantiomer 2
28
10. For an analysis of the influence of drug lipophilicity on off-target pharmacology
and in vivo toxicological outcomes, see: (a) Leeson, P. D.; Springthorpe, B. Nat.
Rev. Drug Dis. 2007, 6, 881; (b) Hughes, J. D.; Blagg, J.; Price, D. A.; Bailey, S.; De
Crescenzo, G. A.; Dalvie, D.; Devraj, R. V.; Doubovetzky, M.; Ellsworth, E.;
Fobian, Y. M.; Gibbs, M. E.; Gilles, R. W.; Grant, D.; Greene, N.; Huang, E.;
Scheme 3. Synthesis of (3R)-pyrrolidines 9a,b. Reagents and conditions: (a) (R)-a-
methylbenzylamine (23), PhMe, molecular sieves 4 Å, 110 °C, 2d; (b) separation by
chromatography; (c) LiAlH4, THF, 0 °C?65 °C, 18 h; (d) 10% Pd/C, 2,5-dihydrotol-
uene, (Boc)2O, EtOH, 85 °C, 2 h; (e) (COCl)2, Me2SO, EtN(iPr)2, CH2Cl2, À78 °C.

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P. V. Fish et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2829–2834
Kreiger-Burke, T.; Lee, L.; Loesel, J.; Nahas, K.; Wager, T.; Whiteley, L.; Zhang, Y.
Bioorg. Med. Chem. Lett. 2008, 18, 4872.
11. Hitchcock, S. A.; Pennington, L. D. J. Med. Chem. 2006, 49, 1.
12. Culbertson, T. P.; Domagala, J. M.; Nichols, J. B.; Priebe, S.; Skeean, R. W. J. Med.
Chem. 1987, 30, 1715.
13. Zheng, X.; Day, C.; Gollamudi, R. Chirality 1995, 7, 90.
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G. A. Bioorg. Med. Chem. Lett. 2006, 16, 4345.
15. For examples of SNRIs, see: (a) Boot, J.; Cases, M.; Clark, B. P.; Findlay, J.;
Gallagher, L. H.; Man, T.; Montalbetti, C.; Rathmell, R. E.; Rudyk, H.; Walter, M.
W.; Whatton, M.; Wood, V. Bioorg. Med. Chem. Lett. 2005, 15, 699; (b) Fish, P. V.;
Deur, C.; Gan, X.; Greene, K.; Hoople, D.; Mackenny, M.; Para, K. S.; Reeves, K.;
Ryckmans, T.; Stiff, C.; Stobie, A.; Wakenhut, F.; Whitlock, G. A. Bioorg. Med.
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coefficient; pKa: measured ionisation constant; HBD: H-bond donor count
(NH+OH); HBA: H-bond acceptor count (N+O); TPSA: topological polar surface
area.
17. For suggested physicochemical property ranges for increasing the potential for
CNS penetration, see Ref. 11. Physicochemical properties for 5l–a: m.wt. 337;
clogP 3.61; LogD7.4 1.2; pKa 9.9 and 4.4; HBD 1; HBA 3; TPSA 34 Å2. 9c: m.wt.
323; clogP 3.05; logD7.4 0.9; HBD 1; HBA 3; TPSA 34 Å2.
18. 3-Piperidines have been reported as NRIs, see: Caprathe, B. W.; Gogliotti, R. D.;
Jennings, R. A.; Simons, L. J. WO Patent Application 023258, 2008.
19. For a comprehensive review, see: Shen, D. D.; Artru, A. A.; Adkison, K. K. Adv.
Drug Delivery Rev. 2004, 56, 1825.
20. For published values of rat CSF to free plasma levels for fluoxetine and
atomoxetine, see: (a) Liu, X.; Smith, B. J.; Chen, C.; Callegari, E.; Becker, S. L.;
Chen, X.; Cianfrogna, J.; Doran, A. C.; Doran, S. D.; Gibbs, J. P.; Hosea, N.; Liu, J.;
Nelson, F. R.; Szewc, M. A.; Deusen, J. V. Drug Metab. Dispos. 2006, 34, 1443; (b)
Kielbasa, W.; Kalvass, J. C.; Stratford, R. Drug Metab. Dispos. 2009, 37, 137.
16. Definition of terms: m.wt.: molecular weight; clogP: calculated partition
coefficient (BIOBYTE software); LogD7.4: measured octanol-buffer distribution