Synthesis, characterization, and biological assessment of the four stereoisomers of the H3 receptor antagonist 5-fluoro-2-methyl-N-[2- methyl-4-(2-methyl[1,3′]bipyrrolidinyl-1′-yl)phenyl]benzamide

Article abstract of DOI:10.1016/j.bmcl.2013.05.068

This Letter describes the asymmetric synthesis of the four stereoisomers (8a-8d) of a potent and highly selective histamine H₃ receptor (H₃R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1, 3′]bipyrrolidinyl-1′-yl) phenyl]be

Full text of DOI:10.1016/j.bmcl.2013.05.068

Bioorganic & Medicinal Chemistry Letters 23 (2013) 4044–4047
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, characterization, and biological assessment of the four
stereoisomers of the H3 receptor antagonist 5-fluoro-2-methyl-N-[2-
methyl-4-(2-methyl[1,30]bipyrrolidinyl-10-yl)phenyl]benzamide
b,
Zhongli Gao a, , William J. Hurst , Etienne Guillot c, Raisa Nagorny b, Marie-Pierre Pruniaux c,
⇑
James A. Hendrix b, Pascal G. George c
a LGCR SMRPD Chemical Research, Sanofi US, 153-1-122, 153 2nd Ave., Waltham, MA 02451, USA
b Sanofi US, 55C-420A, 55 Corporate Drive, Bridgewater, NJ 08807, USA
c Sanofi R&D, Chilly-Mazarin, France
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the asymmetric synthesis of the four stereoisomers (8a–8d) of a potent and highly
Received 4 April 2013
Revised 15 May 2013
Accepted 20 May 2013
Available online 30 May 2013
selective
histamine
H3
receptor
(H3R)
antagonist,
5-fluoro-2-methyl-N-[2-methyl-4-(2-
methyl[1,30]bipyrrolidinyl-10-yl) phenyl]benzamide (1). The physico-chemical properties, in vitro H3R
affinities and ADME of 8a–8d were determined. Stereoisomer 8c (2S,30S) displayed superior in vitro
H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug
safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio
and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Histamine H3 receptor antagonists
Stereochemistry and pharmacological
activity
Asymmetric synthesis
Obesity
In the past decade, histamine H3 receptor (H3R) has emerged as
a promising therapeutic target for the treatment of obesity.1–6
Obesity is a significant health problem worldwide. Global obesity
rates have increased steadily in both developed and emerging
countries over the past several decades with little sign of abating.
Over 1.5 billion people7 worldwide are overweight or obese and
over 40 million children under the age of 5 are overweight. This
condition is associated with a number of co-morbidities including
cardiovascular diseases, type II diabetes mellitus, hypertension,
cancers, and musculoskeletal disorders. Management strategies
for weight reduction in obese individuals include changes in life
style such as exercise and diet, behavioral therapy, and drug treat-
ment, and in certain cases surgical intervention. Drug treatment of-
fers a potential solution, at least as a possible adjunct to diet and
exercise. In the past, several drugs were used as therapy of weight
reduction including thyroid hormone, dinitrophenol, ampheta-
mines and their analogs, for example fenfluramine. At present, orli-
stat8 is the only FDA-approved medication for the longer term
treatment (P24 weeks) of obesity. There exist unmet medical
needs for safe and efficacious anti-obesity treatments.
Previous work9,10 from our laboratories described a series of
compounds, represented by 5-fluoro-2-methyl-N-[2-methyl-4-(2-
methyl[1,30]bipyrrolidinyl-10-yl) phenyl]benzamide (1), (Fig. 1)
which displayed oral activity in a mouse food intake inhibition
model. The compound was potent in in vitro H3R affinity and func-
tional assays across species (human, rhesus monkey, and rat) and
exhibited good in vitro metabolic stability and high permeability
H3C
CH3
H
N
N
N
O
F
H3C
1
rh-H3R binding Ki = 1.2 nM
h-H3R binding Ki = 8.6 nM
r-H3R binding Ki = 16.5 nM
rh-H3R GTPγS EC50 = 1.1 nM
solubility = 2.67 mg/mL
hERG IC50 = 0.48 µM
⇑
Corresponding author. Tel.: +1 781 434 3635.
E-mail addresses: zhongli.gao@sanofi.com (Z. Gao), william.hurst@sanofi.com
(W.J. Hurst).
Tel.: +1 908 981 3723.
Figure 1. Structure of compound 1.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.05.068

Z. Gao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4044–4047
4045
Table 1
in Caco2, no inhibition of key cytochrome P450 isoenzymes (IC50
values >30 M for CYP 1A2, 2C9, 2C19, 2D6, and 3A4), and high
Chiral HPLC analyses of intermediates 6a–6da
l
selectivity towards a panel of 78 GPCRs, ion channels, enzymes,
and kinases, particularly human histamine H1 receptor (h-H1R),
H2 receptor (h-H2R), and H4 receptor (h-H4R) (<50% inhibition @
Stereoisomer
tR (min)
Optical purities (%)
6a
6b
6c
6d
10.92
11.93
8.16
>99
>99
>99
>99
10
lM). However, compound 1 displayed unacceptably high affin-
8.95
ity toward hERG channel (IC50 = 0.48
l
M). Therefore, we needed to
a
continue our optimization to identify a ‘best in class’ type of devel-
opment candidate for treatment of obesity. Realizing that 1 is a
mixture of four stereoisomers, before we embarked on the optimi-
zation, we decided to synthesize all four stereoisomers of 1 in or-
der to determine if a specific stereoisomer retained high H3R
affinity while devoid of hERG channel inhibition. Herein, we de-
scribe the asymmetric synthesis, physico-chemical characteriza-
tions, and ADME properties, as well as biological activities of all
four stereoisomers of 1.
The syntheses of the stereoisomers of 1 were carried out as out-
lined in Scheme 1. The commercially available (R)- or (S)-3-BOC-
pyrrolidin-3-ol (2a) or (2b) (R = H) were transformed into corre-
sponding tosylate 2a or 2b (R = Ts), respectively. These intermedi-
ates (2a and 2b, R = Ts) were condensed with commercially
available (R)- or (S)-2-methyl-pyrrolidines, 3a or 3b, respectively,
to obtain the four optically pure isomers 4a–4d in good yield
(64–68%). These four intermediates were individually treated with
HCl in dioxane to release the free amines 5a–5d, which were con-
densed with 5-fluoro-2-nitrotoluene to yield the four optically
pure intermediates 6a–6d. The optical purities of these four com-
pounds were assessed at this stage using chiral HPLC equipped
Chiral HPLC conditions: instrument used was Mettler-Toledo AutoChem Inc.
Berger SFC Analytix–Minigram; column: Chiralpak AS, 10
M, 250 ꢁ 4.6 mm; elu-
ent: 90% CO2/10% iso-propanol with 0.5% isopropylamine; outlet pressure:
150 bars; flow rate: 5.0 mL/min.; detection: UV 224 nm; injection volume: 20 lL;
concentration: ꢂ1.0 mg/mL.
l
with UV detector. The results (Table 1) showed that the optical
purities were >99% for all four stereoisomers 6a–6d.
The nitro group of intermediates 6a–6d was hydrogenated to ob-
tain the anilines 7a–7d which were coupled with 2-methyl-5-flu-
orobenzoic acid or acid chloride under standard coupling
conditions to obtain the desired final stereoisomers 8a–8d. The
structures of these stereoisomers were characterized spectroscopi-
cally.11 Their physico-chemical properties were also determined
(Table 2). The specific rotations, within experimental error, were
in good alignment as two enantiomeric pairs (8a vs 8b and 8c vs
8d). Crystals of all four stereoisomers were obtained by recrystalli-
zation from DCM and methyl t-butyl ether. The physical states were
characterized as crystlline material for 8a–8d by polarized light
microscopy and X-ray powder diffraction (XRPD). The DSC thermo-
gram of the compounds exhibited one endothermic peak with onset
3'
O
N
N
b
a
2
O
N
OR
*
HN
O
+
O
*
2
3'
4a
4b
4c
4d
R
S
S
R
S
R
S
R
2a: * R
2b: * S
3a: * R
3b: * S
3'
d
3'
N
c
N
HN
. HCl
N
2
O2N
2
2
3'
2
3'
5a
5b
5c
5d
R
S
S
R
S
R
S
R
6a
R
S
S
R
S
R
S
R
6b
6c
6d
3'
N
N
3'
O
e
N
N
2
N
H
2
H2N
2
3'
2
3'
F
8a
R
S
S
R
S
R
S
R
7a
R
S
S
R
S
R
S
R
8b
8c
8d
7b
7c
7d
Scheme 1. Syntheses of the stereoisomers of 1. Reagents and conditions: (a) (1) optically pure (R) or (S)- 3-Boc-pyrrolidin-3-ol, TsCl, TEA, DMAP, DCM, 75%; (2) optically pure
(R)- or (S)-2-methyl-pyrrolidine, K2CO3, CH3CN, 75 °C, 20 h, 64–68%; (b) 4 M HCl/dioxane, 2 equiv, 100%; (b) 5-fluoro-2-nitrotoluene, K2CO3, DMSO, 85 °C, overnight; (d) H2,
10% Pd/C, MeOH, rt, 4 h, 85%; (e) 2-methyl-5-fluoro-benzoic acid, EDCꢀHCl, HOBt, N-methyl morpholine, DCM, DMF, 0 °C to rt, 82%.

4046
Z. Gao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4044–4047
Table 2
isolated from a CHO cell line stably transfected with the recombi-
nant human H3 receptor (h-H3R), the rhesus monkey H3 receptor
(rh-H3R) or the rat H3 receptor (r-H3R) (Table 3). These stereoiso-
mers were found to be very different in H3R affinity. The affinity
of 8c toward rh-H3R is 59-fold higher than 8d, 48-fold higher than
8a, and 3-fold higher than 8b. The stereoisomer 8c also displayed
higher affinity toward h-H3R and r-H3R than the rest of the stereo-
isomers. The same trend was also observed in functional behavior
(FLPR data, Table 3). These results indicated that 2S stereochemis-
try was preferred for activity (compare 8c vs 8a).13 In contrast,
there was little to no preference in activity for either R or S substit-
uents at 3’-position. All four stereoisomers showed acceptable
in vitro metabolic stabilities. However, the differences were
appreciable. For example, in rat liver microsome preparations, 8c
was 3-fold more stable than 8a.
Physico-chemical characterization of the stereoisomers 8a–8d
8a
8b
8c
8d
Stereochemistry
2R,30S
2S,30R
2S,30S
2R,30R
Specific rotationa
ꢃ28.49° +27.14° +22.70° ꢃ24.41°
Melting pointb (°C)
Solubility in PBS (pH 7.4) (
149.0
g/mL) ND
149.4
88.5
6.3
8.9
3.55
2.09
123.0
293.4
6.3
8.9
3.55
2.09
123.5
ND
6.3
8.9
ND
l
c
pKa1
6.3
8.9
ND
ND
c
pKa2
logPc
logDc
ND
a
Solvent: MeOH; concentration (w/v): compound 8a: 0.516%; compound 8b:
0.560%; compound 8c: 0.540%; compound 8d, 0.504%.
b
Melting points were determined by DSC using instrument of 2910 M DSC V4.4E,
scanning range of ꢃ10 to 300 °C.
c
Determined experimentally. ND = not determined.
Due to the superiority of 8c in affinity and in vitro PK parame-
ters, this stereoisomer was selected for further profiling. The com-
pound showed P450 enzyme inhibition IC50 value >30 lM for all
Table 3
H3R binding affinity, functional antagonism activity, and ADMET characteristics
the isozymes tested (CYP 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4). In
a mouse PK experiment, 8c showed high exposure in plasma
(AUC0–1 of 4000 ng h/mL) and in brain (AUC0–1 = 18,000 ng h/
mL) when dosed orally at 10 mg/kg. The compound showed short
on-board time (p.o., tmax of 0.17 h to plasma, tmax of 1.0 h to brain),
good t1/2 (p.o., plasma t1/2 = 3.6 h, brain t1/2 = 3.5 h) for potential
use in CNS indications (Table 4). The brain to plasma ratio based
on AUC0–24 was 4.6 consistent with that observed in the intrave-
nous study. There was less concern of brain retention of the com-
pound because the brain half life (t1/2 = 3.5 h, p.o.) was in the
desired range.14,15
The behavioral safety of 8c was evaluated orally in mice at 3, 10,
and 30 mg/kg doses. Compound 8c increased tail pinch response
(P10 mg/kg) and slightly increased the body temperature (6 h,
30 mg/kg). At 2 h post dosing, tremors were observed for the
30 mg/kg group only; at 6 h post dosing, increased tail pinch re-
sponse was demonstrated for the 30 mg/kg group. There was no ef-
fect on pupil size or body weight attributable to the administration
of 8c. There were no abnormal clinical signs observed during the
one-week post-dose observation period.
Assays
Species
Compounds
8a
8b
8c
8d
H3R binding Kia (nM)
Rhesus
Human
Rat
Human
Human
Mouse
Rat
121.0
819.7
93.0
7.3
2.5
147.0
300.0
73.7
18.0
11.0
3.4
3.0
H3R FLIPR IC50b (nM)
Microsomal labilityc (%)
0.66
0.0092
0.0060
3.0
19.0
20.0
0.71
7.0
29.0
60.0
5.0
20.0
36.0
8.0
17.0
27.0
a
Binding assay was performed as in Ref. 10; Ki data for all the species were
presented as a range of multiple experiments (n P3). ND = not determined.
Human H3R FLIPR data is reported as an averge of n = 3.
Microsomal lability was performed using human, mouse, and rat liver micro-
somes preparation (in house) incubated at 37 °C for 20 min with 5 lM concentra-
tion of the substrate. The data was expressed as the percentage of the parent
b
c
compounds metabolized.
temperature which was confirmed as a melting event by micro-
scopic hotstage. The TGA thermogram did not show a significant
weight loss for all the stereoisomers 8a–8d.12
The affinity of 8a–8d for the H3R was evaluated in binding as-
In further profiling, it was found that all stereoisomers 8a–8d
displayed similar unwanted hERG affinities (Table 5). This led us
says by displacement of [3H]N-
a-methylhistamine in membranes
Table 4
Pharmacokinetic* parameters of 8c
Cmax (ng/mL)
tmax (h)
AUC(0–1) (ng h/mL)
t1/2 (h)
Cl (L/h/kg)
Vdss (L/kg)
Brain/plasma AUC(0–24) ratio
i.v.
Plasma
Brain
Plasma
Brain
2000
4820
1310
4290
0.083
0.083
0.17
560
2600
4000
2.6
1.6
3.6
3.5
3.6
—
—
5.2
—
—
4.7
4.6
p.o.
1.00
18,000
—
—
i.v. Dosing at 2 mg/kg in 50% 1-methyl-2-pyrrolidinone in saline (1 mg/mL).
p.o. Dosing at 10 mg/kg in 5% DMSO/0.5% MC/0.2% tween 80 (1 mg/mL).
*
PK was run with male C57BL/6 mouse.
Table 5
Safety assessment of 8a–8d
Compound
8a
8b
8c
8d
Stereochemistry
hERG affinitya
2R,30S
43.0
84.3
ND
>30
2S,30R
38.8
88.6
1.8
2S,30S
43.4
84.3
1.1
2R,30R
33.7
77.5
ND
>30
% Inhibition @ 1.0
% Inhibition @ 10
l
M
lM
IC50
IC50
(
(
l
l
M)
M)
Cyp inhibitionb
Ames II
MNT test
>30
>30
Not mutagenic
Negative
Not mutagenic
Negative
Not mutagenic
Negative
Not mutagenic
Negative
a
hERG was determined using patch-clamp technique in the whole-cell configuration on Chinese hamster ovary (CHO) cells stably transfected with the human ERG gene.
ND = not determined.
b
Cytochrome P450 isoenzymes determined: 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4.

Z. Gao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4044–4047
4047
4. Tokita, S.; Takahashi, K.; Kotani, H. J. Pharmacol. Sci. 2006, 101, 12.
5. Esbenshade, T. A.; Fox, G. B.; Cowart, M. D. Mol. Interv. 2006, 6, 77.
6. Hancock, A. A.; Diehl, M. S.; Fey, T. A.; Bush, E. N.; Faghih, R.; Miller, T. R.;
Krueger, K. M.; Pratt, J. K.; Cowart, M. D.; Dickinson, R. W.; Shapiro, R.;
Knourek-Segel, V. E.; Droz, B. A.; McDowell, C. A.; Krishna, G.; Brune, M. E.;
Esbenshade, T. A.; Jacobson, P. B. Inflamm. Res. 2005, 54, S27.
to postulate that the hERG affinity of 1 may arise from the overly
lipophilic nature of the molecule. Different stereochemistry at 2-
methyl[1,30]bipyrrolidinyl-10-yl portion of the molecule could not
provide enough differentiation for hERG channel affinity among
stereoisomers. Therefore, a different strategy to address the hERG
issue should be sought.
7. Nguyen, T.; Lau, D. C. Can. J. Cardiol. 2012, 28, 326.
8. Kang, J. G.; Park, C. Y. Diabetes Metab. J. 2012, 36, 13.
9. Gao, Z.; Hurst, W. J.; Guillot, E.; Czechtizky, W.; Lukasczyk, U.; Nagorny, R.;
Pruniaux, M. P.; Schwink, L.; Sanchez, J. A.; Stengelin, S.; Tang, L.; Winkler, I.;
Hendrix, J. A.; George, P. G. Bioorg. Med. Chem. Lett. 2013, 23, 3416.
10. Gao, Z.; Hurst, W. J.; Guillot, E.; Czechtizky, W.; Lukasczyk, U.; Nagorny, R.;
Pruniaux, M. P.; Schwink, L.; Sanchez, J. A.; Stengelin, S.; Tang, L.; Winkler, I.;
Hendrix, J. A.; George, P. G. Bioorg. Med. Chem. Lett. 2013, 23, 3421.
11. Analytical data: LC method: SYNERGI 2U HYDRO-RP 20 ꢁ 4.0 mm column, 0.1%
TFA in water/acetonitrile 5–40% acetonitrile in 2 min. then, to 95% acetonitrile
at 5 min at flow rate of 1.0 mL/min;
In conclusion, we have developed an asymmetric synthetic
route which allows the syntheses of all four stereoisomers 8a–8d
of a potent and selective H3R antagonist, 5-fluoro-2-methyl-N-[2-
methyl-4-(2-methyl-[1,30]bipyrrolidinyl-10-yl)phenyl]benzamide
(1) individually with high optical activity (optical purity >99% for
all four stereoisomers). The physico-chemical properties, in vitro
H3R affinities and ADME of 8a–8d were characterized. Stereoiso-
mer 8c (2S,30S) was selected for further profiling in in vivo PK
and drug safety. Compound 8c displayed superior in vitro H3R
affinity and functional antagonism over other three stereoisomers
and excellent PK properties with high exposure, desired brain to
plasma ratio and reasonable brain half life. There was less concern
on brain retention of this compound. However, all stereoisomers
displayed similar unwanted hERG affinities. These results should
direct the future optimization to focus on 2S configuration (as seen
in 8c) by introducing polar functional groups to lower logP and to
increase total polar surface area (TPSA) in order to address hERG
channel affinity issue. The continued optimization is currently
underway and the progress will be communicated in due course.
Compound 8a: LC–MS: RT = 1.61 min, MS: 396 (M+H+).
1H NMR (DMSO-d6, 300 MHz), d (ppm): 7.50 (d, 7.4 Hz, 1H), 7.25 (m, 1H), 7.05
(m, 2H), 6.40 (m, 2H), 3.51–3.20 (m, 5H), 3.00 (m, 1H), 2.78 (m, 1H), 2.58 (m,
1H), 2.50 (s, 3H), 2.28 (s, 3H), 2.05–1.95 (m, 3H), 1.95–1.65 (m, 3H), 1.45 (m,
1H), 1.08 (d, 6.4 Hz, 3H).
Compound 8b: LC–MS: RT = 1.61 min, MS: 396 (M+H+).
1H NMR (DMSO-d6, 300 MHz), d (ppm): 7.50 (d, 7.4 Hz, 1H), 7.25 (m, 1H), 7.05
(m, 2H), 6.40 (m, 2H), 3.51–3.20 (m, 5H), 3.00 (m, 1H), 2.78 (m, 1H), 2.58 (m,
1H), 2.50 (s, 3H), 2.28 (s, 3H), 2.05–1.95 (m, 3H), 1.95–1.65 (m, 3H), 1.45 (m,
1H), 1.08 (d, 6.4 Hz, 3H).
Compound 8c: LC–MS: RT = 2.14 min, MS: 396 (M+H+).
1H NMR (DMSO-d6, 300 MHz), d (ppm): 7.48 (d, 7.4 Hz, 1H), 7.22 (m, 1H), 7.04
(m, 2H), 6.42 (m, 2H), 3.53 (m, 1H), 3.42–3.18 (m, 4H), 3.05 (m, 1H), 2.81 (m,
1H), 2.54 (m, 1H), 2.49 (br s, 3H), 2.28 (br s, 3H), 2.20–1.95 (m, 3H), 1.9–1.9 (m,
2H), 1.60 (br, 1H), 1.48 (m, 1H), 1.15 (d, 6.0 Hz, 3H).
Compound 8d: LC–MS: RT = 2.13 min, MS: 396 (M+H+).
1H NMR (DMSO-d6, 300 MHz), d (ppm): 7.48 (d, 7.4 Hz, 1H), 7.22 (m, 1H), 7.04
(m, 2H), 6.42 (m, 2H), 3.53 (m, 1H), 3.42–3.18 (m, 4H), 3.05 (m, 1H), 2.81 (m,
1H), 2.54 (m, 1H), 2.49 (br s, 3H), 2.28 (br s, 3H), 2.20–1.95 (m, 3H), 1.9–1.9 (m,
2H), 1.60 (br, 1H), 1.48 (m, 1H), 1.15 (d, 6.0 Hz, 3H).
Acknowledgments
The authors are grateful to Sanofi R&D management for the
strong support, to the H3R project team members for their contri-
butions, to the Sanofi Analytical Department for their support on
analytical studies in confirmation of the structures, and to the
Sanofi DMPK department for their generous support.
12. Thermogravimetry analysis (TGA) and differential scanning calorimetry (DSC)
conditions: TGA data was acquired using a TA instrument TGA Q500 with
thermal advantage (v4.9.3) and processed using universal analysis (v4.4A);
atmosphere: nitrogen at 40 cc/min for balance and 60 cc/min for sample; rate:
10 °C/min. DSC data was acquired using a TA instruments DSC Q2000 with
thermal advantage (v4.9.3) and processed using universal analysis (v4.4A);
atmosphere: nitrogen at 50 cc/min; Crimped Tzero non-hermetic aluminum
pan and lid with pinhole; rate: 10 °C/min.
13. Nersesian, D. L.; Black, L. A.; Miller, T. R.; Vortherms, T. A.; Esbenshade, T. A.;
Hancock, A. A.; Cowart, M. D. Bioorg. Med. Chem. Lett. 2008, 18, 355.
14. Barbier, A. J.; Berridge, C.; Dugovic, C.; Laposky, A. D.; Wilson, S. J.; Boggs, J.;
Aluisio, L.; Lord, B.; Mazur, C.; Pudiak, C. M.; Langlois, X.; Xiao, W.; Apodaca, R.;
Carruthers, N. I.; Lovenberg, T. W. Br. J. Pharmacol. 2004, 143, 649.
15. Zulli, A. L.; Aimone, L. D.; Mathiasen, J. R.; Gruner, J. A.; Raddatz, R.; Bacon, E. R.;
Hudkins, R. L. Bioorg. Med. Chem. Lett. 2012, 22, 2807.
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