2,6-Disubstituted N-arylsulfonyl piperidines as γ-secretase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2006.09.094

A novel piperidine series of γ-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in

Full text of DOI:10.1016/j.bmcl.2006.09.094

Bioorganic & Medicinal Chemistry Letters 17 (2007) 57–62
2,6-Disubstituted N-arylsulfonyl piperidines
as c-secretase inhibitors
Dmitri A. Pissarnitski,a,* Theodros Asberom,a Thomas A. Bara,a Alex V. Buevich,b
John W. Clader,a William J. Greenlee,a Henry S. Guzik,a Hubert B. Josien,a Wei Li,a
Michael McEwan,c Brian A. McKittrick,a Terry L. Nechuta,a Eric M. Parker,d
Lisa Sinning,a Elizabeth M. Smith,a Lixin Song,d Henry A. Vaccaro,a Johannes H. Voigt,b
Lili Zhang,d Qi Zhangd and Zhiqiang Zhaoa
aDepartment of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA
bDepartment of Structural Chemistry, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA
cSummer Internship Program, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA
dDepartment of Central Nervous System, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA
Received 24 August 2006; revised 28 September 2006; accepted 29 September 2006
Available online 4 October 2006
Abstract—A novel piperidine series of c-secretase inhibitors, potentially useful for the treatment of Alzheimer’s disease, is disclosed.
SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the
chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC50’s in the single-digit
nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.
Ó 2006 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD) is a progressive neurodegener-
ative disorder accompanied by memory decline, cogni-
tive impairment, and visual-spatial disorientation, for
which no effective treatment exists today. Postmortem
brain analysis of AD patients reveals extensive forma-
tion of neurofibrillary tau protein tangles and amyloid
plaques. The latter are formed by the aggregation of a
highly insoluble amyloid-b peptide (Ab) which is pre-
dominantly composed of a sequence of 40 or 42 amino
acids. Over-expression of Ab in the brain of AD patients
is thought to be the major cause of AD pathology.1,2 Ab
is formed from a larger amyloid precursor protein (APP)
by the action of two proteolitic enzymes, termed b- and
c-secretases. Accordingly, an inhibitor of either b- or
c-secretase3 may serve as a treatment of AD.
studied doses.5 These encouraging results prompted us
to disclose our SAR studies on cyclic sulfonamides.
The preceding paper6 described the discovery of a tetra-
hydroquinoline series I of c-secretase inhibitors starting
from a moderately active lead 1 (Fig. 1). Presently, we
describe a related series II based on a sulfonylated piper-
idine core.
One of the synthetic complications of piperidines II is a
possibility of cis- and trans-relative stereochemistry be-
tween the R3 group and the carbamate side chain. At
the outset, a few members of the trans-series 5a and b
and cis-series 7a and b with a methyl substituent as the
R3 group were prepared according to Scheme 1.
For the synthesis of 5a and b, N-Boc-2-methylpiperidine
was deprotonated using Beak’s conditions7 and
quenched with dimethylformamide to furnish trans-
2,5-disubstituted piperidinyl aldehyde 2.8 After reduc-
tion of the aldehyde to primary alcohol, the Boc group
was cleaved and the resulting alcohol was protected as
a TBS ether, providing 3. The amino group of 3 was
sulfonylated using 4-chlorobenzenesulfonylchloride
and triethylamine as the base, TBS group was removed
Several types of c-secretase inhibitors have been report-
ed recently.4 At least one compound entered in the
Phase I clinical trials for AD was well tolerated at the
Keywords: c-Secretase; Alzheimer’s disease; Inhibitor; Sulfonamide;
Piperidine; Carbamate; Mosher ester.
*
Corresponding author. E-mail: Dmitri.Pissarnitski@spcorp.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.09.094

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D. A. Pissarnitski et al. / Bioorg. Med. Chem. Lett. 17 (2007) 57–62
Table 1. Preference of cis-substitution at the piperidine ring
Compound Series
NR1R2
R3
Ab40
IC50 (lM)
5a
7a
8a
5b
7b
8b
9
II-trans
Me
10.62
1.97
0.68
6.42
0.57
0.27
15.42
II-cis
Me
N/A
Me
Me
N/A
H
I
II-trans
II-cis
I
Figure 1. The origin of the piperidine series of c-secretase inhibitors.
II
N/A, not applicable.
sponding tetrahydroquinoline analogs 8a and b with
identical NR1R2 groups6 (Table 1). Interestingly, cis-di-
substituted piperidines 7a and 7b were approximately 5-
to 10-fold more active than their trans-congeners 5a and
5b. Both 5a,b and 7a,b were much more active than
piperidine 9 which lacked the R3 group, thus underlining
the importance of this substituent for the binding inter-
action with the enzyme. Based on the activity, the cis-di-
substituted series was selected for further advancement
(Table 2).
Cyclic amines bearing a basic nitrogen center at the
right-hand side provided more active compounds (7c,d
vs 7b). Additional improvement in potency was achieved
by applying ethyl as the R3 substituent (13a and b). Syn-
thesis of compounds 13a and b started from the coupling
of the methyl ester of commercial 6-bromo-2-pyridine-
carboxylic acid with vinyltributyltin under Stille condi-
tions (Scheme 2).10 Resulting pyridine 10 was
hydrogenated over platinum dioxide followed by sulf-
onylation, reduction of the ester group with LAH to
the alcohol, and conversion of the latter to the carbon-
ate 12. Transformation of 12 to the carbamates 13a
and b was accomplished as previously described.
Scheme 1. Synthesis of trans- and cis-2,6-disubstituted piperidines.
Reagents and conditions: (i) sec-BuLi, Et2O, TMEDA, À78 °C, then
DMF; (ii) a—NaBH4, THF; b—TFA, DCM; c—TBSCl, imidazole,
THF; d—4-chlorobenzenesulfonylchloride, DCM, Et3N; (iii) a—
TBAF, THF; b—4-NO2–C6H4–O(CO)Cl, Py (3 equiv), THF/
CH3CN = 2:1; (iv) HNR1R2, THF or DCM; (v) K2CO3, MeOH.
with TBAF, and the primary alcohol was converted to
4-nitrophenylcarbonate. The resulting intermediate 4
could be stored for months at room temperature with-
out signs of decomposition and conveniently provided
the final carbamates 5a and b by the displacement of
4-nitrophenol with amines. For the preparation of cis-
disubstituted piperidines 7a and b, aldehyde 2 was epi-
merized using potassium carbonate in methanol to pro-
vide 6, which was processed in the analogous fashion.
Since tetrahydroquinolines I contain an aromatic region
on the left-hand side of the molecule which is important
for activity, we chose to append an aromatic R3 off the
piperidine scaffold. The syntheses of benzyl- and phenyl-
substituted compounds 18a,b and 21a–d are shown in
Scheme 3. Commercial 2,6-dibromopyridine and
known11 6-bromo-pyridine-2-carboxaldehyde were used
as the starting materials. Both sequences utilized selec-
tivity in catalytic hydrogenation of the pyridine over
the phenyl when atmospheric pressure of hydrogen
was used (rubber balloon).
Compounds 5a,b and 7a,b showed bioactivity in the
c-secretase assay9 albeit were less potent than corre-

D. A. Pissarnitski et al. / Bioorg. Med. Chem. Lett. 17 (2007) 57–62
59
Table 2. SAR of piperidine series II-cisa
Compound
NR1R2
R3
Ab40 IC50 (lM)
7c
Me
0.219
7d
Me
Et
0.076
0.159
13a
13b
18a
Et
0.034
12.30
Bn
18b
21a
Bn
Ph
4.77
0.071
21b
21c
21d
Ph
Ph
Ph
0.067
0.037
0.016
22a
22b
2-F–Ph
2-F–Ph
0.017
0.008
23a
23b
3-F–Ph
3-F–Ph
0.038
0.026
(continued on next page)

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D. A. Pissarnitski et al. / Bioorg. Med. Chem. Lett. 17 (2007) 57–62
Table 2 (continued)
Compound
NR1R2
R3
Ab40 IC50 (lM)
23c
3-F–Ph
0.013
23d
3-F–Ph
0.011
0.003
0.083
0.028
0.010
0.036
0.007
0.004
0.026
0.008
(À)-23d
(+)-23d
24a
3-F–Ph
3-F–Ph
2,5-Di-F–Ph
2,5-Di-F–Ph
3,5-Di-F–Ph
3,5-Di-F–Ph
3,5-Di-F–Ph
3,4-Di-F–Ph
3,4-Di-F–Ph
24b
25a
25b
25c
26a
26b
a All compounds are racemic unless stated otherwise.
While the activity of benzyl-substituted compounds 18a
and b dropped precipitously (Table 2), corresponding
phenylpiperidines 21a–d showed an improvement in
potency, reaching the double-digit nanomolar level.
Since introduction of a fluorine atom in the aromatic re-
gion of I led to an improvement of potency,6 the same
substituent was introduced into various positions of
the phenyl ring of 21a–d. As was expected, the resulting
mono- and difluorinated compounds 22–26 showed im-
proved potency with IC50’s in the single-digit nanomolar
range.
In order to elucidate the requirements of the absolute
stereochemistry, synthetic intermediate 27 was resolved
by chromatography on a ChiralpakTM OD column12
using 15% IPA in hexanes, and both enantiomers of
23d were prepared in a pure form (Fig. 2). The early
eluting enantiomer of 27 gave rise to the (À)-enantio-
mer of 23d which was more active (Table 2) with
eudismic ratio of approximately 27. The absolute ste-
reochemistry of (À)-27, and therefore (À)-23d, was as-
signed using Mosher’s method, which relies upon the
assessment of proton NMR chemical shift differences

D. A. Pissarnitski et al. / Bioorg. Med. Chem. Lett. 17 (2007) 57–62
61
Scheme 2. Synthesis of compounds 13a and b. Reagents and condi-
tions: (i) (a) vinyltributyltin, Pd(PPh3)4, DMF, 90 °C; (ii) a—H2, cat
PtO2, 50 psi, MeOH; b—4-chlorobenzenesulfonylchloride, Py; (iii)
a—LAH, THF, 0 °C; b—4-NO2–C6H4–O(CO)Cl, Py (3 equiv),
THF/CH3CN = 2:1; (iv) HNR1R2, THF or DCM.
Figure 2. Stereochemical analysis of the series.
Scheme 3. Introduction of the aromatic groups to the piperidine core.
Reagents and conditions: (i) BuLi (1 equiv), ether, À78 °C, then DMF;
(ii) Et3SiH, TFA, DCM, 80 °C, sealed tube; (iii) BuLi, THF, À78 °C,
then DMF; (iv) 1 atm H2, PtO2, MeOH/AcOH = 2:1; (v) a—TMSOTf,
Et3N, DCM; b—4-chlorobenzenesulfonylchloride, DCM, Et3N; c—
HCl, MeOH; d—4-NO2–C6H4–O(CO)Cl, Py (3 equiv), THF/
CH3CN = 2:1; e—HNR1R2, THF or DCM; (vi) a—NaBH4, THF;
b—PhB(OH)2, cat Pd(PPh3)4, Na2CO3, toluene/EtOH = 6:3, 90 °C,
10 h.
behavior of DdSR is consistent with the absolute ste-
reochemistry of 28 and 27 as drawn in Figure 2.
In order to assess the energy difference between the
preferred and other conformations of the piperidine
ring, ab initio calculations14 for model compounds
29 and 30 (Fig. 2) were performed (B3LYP/6-31G**
optimization; B3LYP/ CC_PVTZ(-F)++ single point
energy). For 29 and 30, the 2,6-diaxial chair-like con-
formation had the lowest energy in agreement with
the NMR experiment, followed by twist-conforma-
tions which were 4 kcal/mol higher in energy. The
2,6-diequatorial chair-like conformation was 9 kcal/
mol above the energy of the diaxial conformation.
The preference for the diaxial conformation could be
explained by the sp2-character of the piperidine
nitrogen.15
(DdSR) between S and R esters of 2-methoxy-2-phenyl-
2-(trifluoromethyl) acetic acid (MTPA) and the ana-
lyte.13 Alcohol (À)-27 was esterified using both (R)-
and (S)-MTPA. Analysis of the vicinal proton–proton
J-coupling constants and NOEs of the resulting
MTPA esters (À)-28 revealed a chair-like conforma-
tion of the piperidine ring, with the ester side chain
and 3-fluorophenyl substituent both being axial. Com-
plete NOE analysis (not shown) also led to the unam-
biguous assignment of protons Ha and Hb. The
difference in chemical shifts DdSR between the related
protons of (S)- and (R)-MTPA derivatives was then
evaluated. For the protons on the right of the MTPA
plane (e.g., Hb and H2) DdSR was positive, while for
the proton Ha on the left it was negative. Based on
the empirical rules proposed in the literature,13 this
In conclusion, we discovered a novel series of c-secretase
inhibitors based on 2,6-disubstituted N-arylsulfonylpi-
peridine core II. cis-Relative stereochemistry of the sub-
stituents at the piperidine ring was established as a
requirement for the potency. Absolute stereochemistry
of the active enantiomer was assigned by Mosher’s
NMR analysis of a synthetic precursor 27. Combination
of NMR experiments and ab initio calculations points to

62
D. A. Pissarnitski et al. / Bioorg. Med. Chem. Lett. 17 (2007) 57–62
Med. Chem. Lett. 2003, 13, 179; Rishton, G. M.; Retz,
D. M.; Tempest, P. A.; Novotny, J.; Kahn, S.; Treanor,
J. J. S.; Lile, J. D.; Citron, M. J. Med. Chem. 2000, 43,
2297.
the chair-like 2,6-diaxial conformation of the inhibitors
as being predominant.
5. Siemers, E. R.; Quinn, J. F.; Kaye, J.; Farlow, M. R.;
Porsteinsson, A.; Tariot, P.; Zoulnouni, P.; Galvin, J. E.;
Holtzman, D. M.; Knopman, D. S.; Satterwhite, J.;
Gonzales, C.; Dean, R. A.; May, P. C. Neurology 2006,
66, 602.
Acknowledgments
The authors are indebted to Drs. T.-M. Chan, A. Evans,
and R. Osterman for the NMR support, and to the
group of Dr. J. Wong for the scale up of the synthetic
intermediates.
6. Asberom, T. Bioorg. Med. Chem. Lett. (in press),
doi:10.1016/j.bmcl.2006.09.064.
7. Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
8. Chackalamannil, S.; Davies, R. J.; Wang, Y.; Asberom,
T.; Doller, D.; Wong, J.; Leone, D.; McPhail, A. T.
J. Org. Chem. 1999, 64, 1932.
References and notes
9. Zhang, L.; Song, L.; Terracina, G.; Liu, Y.; Pramanik, B.;
Parker, E. Biochemistry 2001, 40, 5049.
10. Stille, J. K. Pure Appl. Chem. 1985, 57, 1771.
11. Iida, T.; Wada, T.; Tomimoto, K.; Mase, T. Tetrahedron
Lett. 2001, 42, 4841.
1. Selkoe, D. J.; Schenk, D. Annu. Rev. Pharmacol. Toxicol.
2003, 43, 545.
2. Wolfe, M. S. J. Med. Chem. 2001, 44, 2039.
3. Taylor, K. W.; Wolfe, M. S. J. Neurosci. Res. 2003, 74,
353.
12. Chiral Technologies Inc., 800 North Five Points Road,
West Chester, PA 19380, USA.
13. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H.
J. Am. Chem. Soc. 1991, 4092.
4. Fuwa, H.; Hiromoto, K.; Takahashi, Y.; Yokoshima, S.;
Kan, T.; Fukuyama, T.; Iwatsubo, T.; Tomita, T.;
Natsugari, H. Bioorg. Med. Chem. Lett. 2006, 16, 4184;
Churcher, I.; Beher, D.; Best, J. D.; Castro, J. L.;
Clarke, E. E.; Gentry, A.; Harrison, T.; Hitzel, L.; Kay,
E.; Kerrad, S.; Lewis, H. D.; Morentin-Gutierrez, P.;
Mortishire-Smith, R.; Oakley, P. J.; Reilly, M.; Shaw,
D. E.; Shearman, M. S.; Teall, M. R.; Williams, S.;
Wrigley, J. D. J. Bioorg. Med. Chem. Lett. 2006, 16,
280; Teall, M.; Oakley, P.; Harrison, T.; Shaw, D.; Kay,
E.; Elliott, J.; Gerhard, U.; Castro, J. L.; Shearman, M.;
Ball, R. G.; Tsou, N. N. Bioorg. Med. Chem. Lett. 2005,
15, 2685; Churcher, I.; Ashton, K.; Butcher, J. W.;
Clarke, E. E.; Harrison, T.; Lewis, H. D.; Owens, A. P.;
Teall, M. R.; Williams, S.; Wrigley, J. D. J. Bioorg.
14. Jaguar 6.0, Schrodinger, LLC, Portland, Oregon, 2005.
15. The four related cis-2,6-dialkyl piperidine amides in the
Cambridge Crystallographic Database all display a 2,6-
diaxial conformation, while the 13 cis-2,6-dialkyl piperi-
dines with a basic sp3-ring nitrogen all display a 2,6-
diequatorial conformation. Cambridge Structural Data-
base v. 5.27, CCDC, Cambridge, UK; entry id’s of hits:
sp2-N: BOAYPI, BZOPIP, FOKMUO, ROHGAW—sp3-
N: BEZJEW, BOVDEV, CALQIQ, CTMPIP, FEMVOI,
HIMBHM, MUFCEV, SUZBIY, SUZBOE, VUHFEJ,
ZINMUE, ZUZXUN, ZZZSMK01.