Discovery of 2,4,6-trisubstituted N-arylsulfonyl piperidines as γ-secretase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2007.09.006

Development of cis-2,4,6-trisubstituted piperidine N-arylsulfonamides as γ-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported.

Full text of DOI:10.1016/j.bmcl.2007.09.006

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 17 (2007) 6290–6294
Discovery of 2,4,6-trisubstituted N-arylsulfonyl piperidines
as c-secretase inhibitors
Hongmei Li,a,* Theodros Asberom,a Thomas A. Bara,a John W. Clader,a
William J. Greenlee,a Hubert B. Josien,a Mark D. McBriar,a Amin Nomeir,b
Dmitri A. Pissarnitski,a Murali Rajagopalan,a Ruo Xu,a Zhiqiang Zhao,a
Lixin Songc and Lili Zhangc
aDepartment of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
bDepartment of Drug Safety and Metabolism, Schering-Plough Research Institute, 2015 Galloping Hill Road,
Kenilworth, NJ 07033, USA
cDepartment of Neurobiology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Received 18 July 2007; revised 27 August 2007; accepted 4 September 2007
Available online 7 September 2007
Abstract—Development of cis-2,4,6-trisubstituted piperidine N-arylsulfonamides as c-secretase inhibitors for the potential treat-
ment of Alzheimer’s disease (AD) is reported.
Ó 2007 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD), the most common form of
dementia, is progressive and irreversible. It is estimated
that about five million Americans suffer from this dis-
ease, and about 360,000 people are newly diagnosed
every year.1 Due to its significant financial burden on
the healthcare system, research on the treatment of
AD has drawn increasing attention from academia and
industry. At the moment, one of the major hypotheses
for the progression of AD is the chronic imbalance
between b-amyloid peptide (Ab) production and Ab
clearance resulting in the extracellular accumulation of
Ab. Subsequent plaque formation in the brain leads to
neurodegeneration, dementia, and ultimately death.
The release of Ab is the result of sequential cleavage
of b-amyloid precursor protein (APP) by two proteases,
b-secretase and c-secretase.2 Because of its central role
in the production of Ab peptide, c-secretase was pro-
posed as an effective target for treatment of AD. To
date, several series of c-secretase inhibitors have been
identified.3
The preceding papers from our research group disclosed
cyclic sulfonamides and 2,6-disubstituted N-arylsul-
fonylated piperidines as potent c-secretase inhibitors.4,5
However, potential drug–drug interactions caused by
CYP inhibition remained an issue in these series, since
aging patients are often under multiple medications.
Interaction of drugs with CYP3A4 has been linked to
lipophilicity and the presence of basic amines.6 During
SAR studies, introduction of small alkyls at the R1 posi-
tion and modification of right-hand side chains substan-
tially reduced CYP3A4 inhibition (Fig. 1). However,
these improvements were still not sufficient to alleviate
the undesired interactions. We envisioned that decreas-
ing clogP by introducing substitution such as –OCH3
Keywords: Alzheimer’s disease; N-Arylsulfonamide; c-Secretase
inhibitor.
*
Corresponding author. Tel.: +1 908 740 6648; e-mail:
hongmei.li@spcorp.com
Figure 1. Introduction of small alkyls to reduce CYP3A4 inhibiton.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.09.006

H. Li et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6290–6294
6291
or –OH, on the piperidine ring could reduce the
CYP3A4 inhibition in the piperidine sulfonamide series.
Herein, we report 2,4,6-trisubstituted piperidine N-aryl-
sulfonamides with reduced CYP3A4 liability. Based on
the previous results,5 the ethyl group was chosen as
the left-hand side chain. Synthesis of compounds Ia
started with preparation of diene 1 and dienophile 2 sep-
arately (Scheme 1). Propionaldehyde was reacted with
(acetylmethylene) triphenylphosphorane,7 followed by
reaction with NaHMDS, and TBSCl in THF to provide
diene 1. Glycine ethyl ester was reacted with 4-chloro-
benzenesulfonyl chloride in a mixture of pyridine/
DCM, followed by bromination and elimination of
HBr to generate dienophile 2.8 Diene 1 and dienophile
2 were combined in THF and stirred at rt overnight,
and the Diels–Alder adduct was treated with concen-
trated HCl in DCM to regioselectively afford 3 as a
separable mixture of diastereomers in favor of the cis-
adduct (cis/trans = 3/1). The cis-diastereomer was
reduced to alcohol 4 with NaBH4 as a mixture of diaste-
reomers at C-4 (cis/trans > 4/1), which were separated by
column chromatography and methylated with CH3I in
the presence of Ag2O.9 Reduction of the ethyl ester with
LAH, conversion of the alcohol to p-nitrophenyl car-
bonate, and reaction with different optimized right-hand
sides5 provided carbamates Ia.
Scheme 2. Reagents and conditions: (a) LAH, THF, 0 °C; (b) p-NO2-
PhCOCl, CH3CN, Py; (c) R1R2NH, DCM; (d) MsCl, Et3N, DCM; (e)
CsOAc, DMAP, toluene, reflux; (f) K2CO3, CH3OH.
Ib (Scheme 2). Also, the alcohol 4-cis was treated with
MsCl, and the ethyl ester was reduced to alcohol with
LAH. The mesylate was displaced with CsOAc in tolu-
ene under reflux,10 and the primary alcohol was con-
verted to p-nitrophenyl carbonate 7. Carbonate 7 was
reacted with amines, followed by hydrolysis of the ace-
tate with K2CO3 providing compounds Ic (Scheme 2).
Alternatively, the alcohol 4-cis was reduced with LAH
directly, followed by transformation of the primary
alcohol selectively as in Scheme 1, giving compounds
The influence of 4-substitution on c-secretase inhibition
and CYP3A4 is summarized in Table 1. Comparing
with similar 2,6-disubstituted analogs, the c-secretase
inhibition was lost completely upon introduction of
4-OCH3 (11, 12, 16, and 17). The free hydroxyl at
zC-4 resulted in a similar c-secretase inhibition (13,
18, and 19). In both cases, CYP3A4 inhibition was de-
creased, with the more polar hydroxyl analog provid-
ing
validating our hypothesis.
a
dramatic reduction in CYP inhibition,
Encouraged by the results, the 4-OH was also intro-
duced in both cyclopropyl carbamate and cyclopropyl
amide series, based on previous observation that intro-
duction of cyclopropyl group helped boost the c-secre-
tase inhibition ꢀ5- to 20-fold.4,5 Preparation of
compounds IIa also began with the synthesis of diene
21 and dienophile 22 (Scheme 3).11 The Diels–Alder
product was obtained favoring the cis-adduct (cis/
trans = 5/1) with desired regioselectivity. It was treated
with concentrated HCl in DCM, followed by reduction
with NaBH4 in the presence of CeCl3Æ7H2O to provide
2,4,6-cis-trisubstituted alcohol 23 exclusively. Alcohol
23 was acetylated, followed by desilylation of the ter-
tiary alcohol to provide 24. The cyclopropyl alcohol
24 was converted to carbamate via the method described
in Scheme 1, followed by deacetylation to provide com-
pounds IIa.
Scheme 1. Reagents and conditions: (a) (acetylmethylene)triphenyl-
phosphorane, reflux, DCM, 60 °C, overnight; (b) NaHMDS, TBSCl,
THF, ꢁ78 °C–rt; (c) 4-chlorobenzenesulfonyl chloride, Py/DCM (1/1),
0 °C–rt; (d) Br2, CCl4, reflux; (e) NaH, THF, 0 °C; (f) overnight, rt,
THF; (g) concd HCl, DCM; (h) NaBH4, CeCl3Æ7 H2O, EtOH; (i)
Ag2O, CH3I, Et2O, 80 °C; (j) LAH, THF, 0 °C; (k) p-NO2-PhCOCl,
CH3CN, py; (l) R1R2NH, DCM.

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H. Li et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6290–6294
Table 1. Structure–activity relationships of carbamatesa
Compound
NR1R2
R3
R4b
Memb Ab40c
IC50 (nM)
CYP3A4d
IC50 (lM)
8
9
Et
H
34.0
5.2
N/A
1.2
c-Pr
i-Pr
Et
H
10
11
12
13
H
18.5
783
1.3
5.0
cis-OCH3
trans-OCH3
cis-OH
Et
Et
>1000
28.4
3.4
24.3
14
15
16
17
18
19
c-Pr
i-Pr
Et
H
71.1
0.3
0.3
H
103.5
>1000
>1000
154.5
310.1
cis-OCH3
trans-OCH3
cis-OH
trans-OH
30.0
10.1
15.6
30.0
Et
Et
Et
a All compounds are racemic mixtures.
b cis- and trans- relative to 2,6-disubstitution on the piperidine ring.
c Data for inhibition of Ab40 were measured by use of membrane-based preparation of c-secretase.
d Values were determined after 30 min pre-incubation with compound.
The synthesis of the cyclopropyl amide is shown in
Scheme 4. Commercially available 2,3-dihydrofuran
was treated with concentrated HCl in water,12 and
the resultant lactol was reacted with formaldehyde to
generate 31.13 Protection of the alcohol and reduction
of aldehyde provided compound 32. After cyclopropa-
nation14 and Swern oxidation,15 cyclopropyl aldehyde
33 was obtained. Wittig reaction with 33 provided
the a,b-unsaturated ketone,7 which was transformed
to diene 34 by using the previous protocol. Again,
the Diels–Alder reaction followed by hydrolysis gave
the correct 2,6-disubstituted piperdine regioisomer,
favoring the trans-diastereomer (trans/cis = 2/1). Fol-
lowing chromatographic separation, the cis-isomer
was reduced with NaBH4 to provide compound 35 as
a single diastereomer. The 4-OH was protected with
the acetate, followed by removal of TBDPS, and oxi-
dation of the primary alcohol gave the acid 36. Then
the 4-OH was unmasked, and the acid was coupled
with amines in the presence of HATU and i-Pr2EtN
to afford amides IIb.
The biological results are shown in Table 2. As expected,
in either series, the introduction of 4-OH substitution on
piperidine ring helped decrease the CYP3A4 inhibition
while maintaining high c-secretase inhibition.
Scheme 3. Reagents and conditions: (a) imidazole, TBSCl, DMF/
DCM; (b) DIBAL, THF, 0 °C; (c) (COCl)2, DMSO, DCM, ꢁ78 °C;
(d) (acetylmethylene) triphenylphosphorane, reflux, DCM, 60 °C,
overnight; (e) NaHMDS, TBSCl, THF, ꢁ78 °C–rt; (f) 4-chloroben-
zenesulfonamide, sodium p-toluenesulfinate, HCO2H, H2O; (g) sat.
Na2CO3, DCM; (h) reflux, toluene, overnight; (i) concd HCl, DCM,
0 °C; (j) NaBH4, CeCl3Æ7H2O, EtOH, 0 °C; (k) Ac2O, DMAP, Py; (l)
TBAF, THF, 0 °C; (m) p-NO2-PhCOCl, CH3CN, pyridine; (n)
R1R2NH, DCM; (o) K2CO3, CH3OH.
In conclusion, by introducing 4-OH on the piperidine
ring with small alkyl groups on the left-hand side and
modified non-basic amines on the right-hand side, we
were able to substantially lessen CYP3A4 inhibition,
while maintaining good c-secretase inhibition in our pre-
viously identified piperidine sulfonamide series.

H. Li et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6290–6294
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Scheme 4. Reagents and conditions: (a) concd HCl, water; (b) butyric acid, dibutylamine, HCHO in water, i-PrOH; (c) imidazole, TBDPSCl,
DMAP, DMF; (d) NaBH4, EtOH, 0 °C; (e) Et2Zn, CH2ICl, DCM, 0 °C–rt; (f) (COCl)2, DMSO, DCM, ꢁ78 °C; (g) (acetylmethylene)
triphenylphosphorane, reflux, DCM, overnight; (h) NaHMDS, TBSCl, THF, ꢁ78 °C–rt; (i) THF, 100 °C, 16 h; (j) concd HCl, DCM, 0 °C; (k)
NaBH4, CeCl3Æ7H2O, THF; (l) Ac2O, p-TsOH (cat.); (m) TBAF, THF; (n) AcNHÆTEMPO, NaCOCl, NaBr=Bu4NþH ꢂ HSO4ꢁ, DCM/H2O; (o)
K2CO3, CH3OH; (p) Amine, HATU, i-Pr2NEt, DMF.
Table 2. Structure–activity relationships of carbamates and amidesa
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b
IC50 (nM)
c
IC50 (l)
25
26
27
28
29
30
3,5-diF-Ph
H
O
O
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c-Pr
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H CH2
OH CH2
9.9
8.1
1.5
11.0
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We sincerely thank Dr. Andy Evans and Ms. Rebecca
Osterman for NMR analysis.

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