Tetracyclic sulfones as potent γ-secretase inhibitors: Synthesis and structure-activity relationship studies

Article abstract of DOI:10.1016/j.bmcl.2010.04.103

Complex tetracyclic sulfones were designed as γ-secretase inhibitors and a stereoselective synthesis was achieved. γ-Secretase activity was seen predominately in the (-) enantiomeric series. Compounds such as 2a and 2b showed remarkable in vitro and in vivo potency.

Full text of DOI:10.1016/j.bmcl.2010.04.103

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3645–3648
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Tetracyclic sulfones as potent c-secretase inhibitors: Synthesis and
structure–activity relationship studies
*
T. K. Sasikumar , Duane A. Burnett, Theodros Asberom, Wen-Lian Wu, Chad Bennett,
David Cole, Ruo Xu, William J. Greenlee, John Clader, Lili Zhang, Lynn Hyde
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Complex tetracyclic sulfones were designed as c-secretase inhibitors and a stereoselective synthesis was
Received 31 March 2010
Revised 20 April 2010
Accepted 22 April 2010
Available online 28 April 2010
achieved.
c
-Secretase activity was seen predominately in the (À) enantiomeric series. Compounds such
as 2a and 2b showed remarkable in vitro and in vivo potency.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
c
-Secretase
Alzheimer’s disease
Sulfone
Alzheimer’s disease (AD) is a neurodegenerative disease affect-
ing millions of people world wide. AD is the fourth major cause of
death in the developed world. The number of Alzheimer’s patients
is reported to be over 35 million-globally. Currently there are no
treatments to delay or halt the progression of the disease available.
Numerous approaches have been taken towards the cure of this
progressive disease. It is widely believed that the beta amyloid
deposits made from oligomeric Ab peptides of 40–42 amino acids
are the fundamental cause of the disease.1 Inhibition of the enzyme
(see Fig. 1 for numbering).6 Recent reports from Merck shows that
a bicyclic sulfonamide bearing a trifluromethylphenyl sulfone moi-
ety (3) is a very potent c
-secretase inhibitor.9,10 The overlay of com-
pounds 1b and 3 suggested that the addition of a fourth ring might
suitably dispose our pharmacophores for maximal potency. We,
thus, decided to incorporate the cyclic sulfonamide moiety to our
benzochromane structure previously discovered, leading to a con-
formationally rigid tetracyclic frame work (2b) as shown inFigure 1.
The synthesis of the tetracyclic compound starts from the
known tricyclic ketone 4 which served as a versatile intermediate
complex
c-secretase by small molecules has been shown to lower
levels of plasma and cortical Ab peptides.2 Several small molecule
for a variety of other c
-secretase inhibitors.6,11 An efficient route to
c
-secretase inhibitors have been identified and some of them have
our tetracycle from ketone 4 was inspired by the camphor sultam
synthesis reported by Davis et al.12 Accordingly, the vinyl sulfon-
amide (5) was prepared in three steps from commercially available
starting materials.13 The copper enolate derived from compound 4
upon 1,4-addition to vinyl sulfonamide 5 under Davis’ reaction
conditions gave us very low isolated yield. However we found that
high dilution conditions omitting the copper salt gave us com-
pound 6 in a reproducible 30–40% average yield. We also observed
significant quantities of a side product whose structure was con-
firmed to be a 1:2 bisalkylated adduct based on the NMR data. Eno-
lates at both positions 7 and 9 of ketone 4 reacted with vinyl
sulfonamide 5 to form 1:2 adduct in this undesired pathway. Any
attempts to reduce the formation of dimeric product were unsuc-
cessful. The desired Michael product 6 could be purified by re-
peated precipitation from hexane–ethyl acetate solvent mixture.
Treatment of compound 6 with 50% TFA/DCM gave the tetracyclic
core structure in 74% isolated yield. It has been found that the
imine double bond isomerized to the tetrasubstituted enamine
position thus destroying the newly created stereocenter at C7.
been progressed to humans clinical studies.3–5
An aryl sulfone core was present in a number of recent publica-
tions on c-secretase inhibitors from various pharmaceutical compa-
nies including Schering-Plough.6–8 The bicyclic chromane sulfone 1a
from our laboratories showed excellent in vitro potency in the
c-secretase assay (membrane IC50 = 42 nM). The potent bicyclic
chromanes prompted the design of conformationally restricted tri-
cyclic analogs such as structure (1b) as shown in Figure 1.6 To our
delight, the newly designed tricyclic sulfone showed remarkable
c
-secretase activity. A series of SAR studies on the cyclohexyl ring
lead us to a number of sulfonamide compounds at position 8 as illus-
trated by structure 1b with an improved -secretase affinity and
c
pharmacokinetic properties. It was also found that small substitu-
tions at position 7 of the tricyclic system was very well tolerated
* Corresponding author. Tel.: +1 908 740 4373; fax: +1 908 740 7164.
E-mail addresses: sasikumartk@yahoo.com, thavalakulamgar.sasikumar@
merck.com (T.K. Sasikumar).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.103

3646
T. K. Sasikumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3645–3648
F
F
F
F
F
4
O
O
O
S
5
H
7
H
CF3
1
O
O
O
O
F
S
F
S
F
S
N
H
N
H
N
H
8
O
O
O S O
O
O S O
O S O
O
9
Cl
Cl
CF3
CF3
1a
1b
2b
3
Figure 1. Tetracycle (2b) design.
The enamine 7 was reduced to compound 8 in 45% isolated yield.
The relative stereochemistry was confirmed by NMR and X-ray
studies of a closely related compound. It has been found that a
small amount of the trans stereoisomer was also isolated from
the reduction reaction. PMB protection of the sulfonamide nitrogen
yield. Compound 2f served as an excellent starting point for a num-
ber of modifications. Allyl derivative 2f was directly converted to
the acid 11 and further derivatised to the amide 12 under standard
conditions.16 Hydroboration of 2f followed by base treatment
afforded compound 13 and then converted to the acid 14 in good
yields.17 Ozonolysis of compound 2f provided aldehyde 15 which
upon reductive amination gave compounds 16a and 16b.
followed by stereoselective a-alkylation and deprotection afforded
the final tetracyclic compounds 2a–h as shown in Scheme 1.14 The
enantiomers were separated on a Chiralcel OD column using iso-
propanol/hexane as eluent. It has been found that the (À) enantio-
The data for the inhibition of Ab40 production measured using
membrane based preparations of
We also assessed the cell permeation properties utilizing whole
cells.15 Unadorned analog
showed good membrane IC50
(30 nM). Simple alkylation products (2a, 2b and 2d) enhanced
the -secretase (both membrane and cellular) affinity by several
c-secretase is shown in Table 1.
mers are significantly more potent at inhibiting
are the corresponding (+) enantiomers.15
c-secretase than
8
During scale up efforts directed to compound 2, reduction of the
double bond of compound 7 proved inconsistent and prompted us
to develop alternate method for the construction of the fourth ring.
To that end, compound 6 was stereoselectively reduced to the trans
alcohol using NaBH4 and the resulting alcohol was converted to the
mesylate. Deprotection of the PMB group using TFA followed by
NaH mediated cyclization afforded the tetracyclic compound 8 in
50–60% overall yield for the four step sequence. Alkylations were
carried out as in Scheme 1 and the final deprotection was achieved
in acidic medium to obtain the tetracyclic compounds.
c
fold. Allyl, crotyl and methoxymethyl derivatives (2e, 2g, 2f)
showed single digit nanomolar affinity, however, the affinity of
cinnamyl derivative 2h dropped fourfold as compared to the crotyl
derivative 2g. Recently carboxylic acid derived
tors have been reported in the literature.18 The tetracyclic
carboxylic acid derivatives 11 and 14 showed good -secretase
c-secretase inhibi-
c
activity. The primary amide 12 derived from compound 11 showed
excellent cellular Ab42 IC50 value. Alcohol derivative 13 also
showed single digit nanomolar potency. Tetracyclic compounds
bearing a basic amine moiety (16a and 16b) are also very well
tolerated.
Further SAR studies were initiated from the PMB protected tet-
racycle 9 as shown in Scheme 2. Stereoselective allylation with al-
lyl iodide followed by deprotection afforded compound 2f in good
h-k (modified synthesis)
F
F
F
F
O
O
O
O
O
O2
S
H
H
H
H
PMB
N
a
b
c
O
O
S
O
F
S
F
F
PMB
F
N
H
O
O
N
H
O S O
O
O S O
O S O
O S
SO2N(PMB)2
5
CF3
CF3
CF3
CF3
4
6
7
8
d
F
F
F
F
F
O
O
O
O
O
H
H
H
R
R
O
f,g
e
O
O
S
O
S
F
S
N
N
H
N
O S
O S O
O S
O
O
OMe
OMe
CF3
CF3
CF3
10
2a-h
9
Scheme 1. Reagents and conditions: (a) LHMDS, THF, then 5, 30–40%; (b) TFA, DCM, 74%; (c) H2, PtO2, EtOAc, 45%; (d) LHMDS, NaI, PMB-Cl, THF, 70%; (e) NaHMDS, RI, THF; (f)
TFA, DCM, 60–70% for two steps; (g) chiral separation on OD column; (h) NaBH4; (i) MsCl, TEA, DCM; (j) TFA, DCM; (k) NaH, DMF, 50–60% for four steps.

T. K. Sasikumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3645–3648
3647
F
F
F
F
F
F
O
O
O
O
O
H
H
H
H
OH
NH2
a,b
c
d
O
O
O
O
S
S
F
S
O
F
S
O
N
N
H
N
H
N
H
O S O
O S O
O S O
O S
O
O
O
O
PMB
CF3
9
CF3
2f
CF3
CF3
12
f
11
e
F
F
F
F
O
O
O
O
O
R1
N
H
H
H
H
H
OH
OH
R2
g
O
O
O
O
F
S
N
F
S
F
S
O
F
S
c
N
H
N
N
H
O
O S O
O S O
O S O
O S
O
O
O
O
H
H
CF3
CF3
CF3
CF3
16 a,b
14
13
15
Scheme 2. Reagents and conditions: (a) NaHMDS, allyl iodide; (b) TFA/DCM, 57% for two steps; (c) RuCl3ÁH2O, NaIO4, EtOAc, CH3CN, H2O, 63%; (d) SOCl2, CHCl3, 50 °C, then
NH3, MeOH, 80%; (e) 9-BBN, H2O2, NaOH, THF, 49%; (f) O3, DCM, then Ph3P, 78%; (g) R1R2NH, NaBH(OAc)3, DCM, 45%.
Table 1
c
-Secretase membrane and cell IC50’s
Compounds 2a and 2b displayed excellent in vitro and cellular
potency and were chosen for further evaluation in a rapid rat PK
study.19 The results of these studies and additional biological prop-
erties are shown in Table 2. The compounds were dosed orally
(10 mg/kg) as a suspension in 20% HPBCD. These compounds
showed moderate exposure with low brain concentration. Com-
pounds 2a and 2b showed no CYP and hERG issues and human
hepatocyte clearance was low. These compounds are also highly
protein bound (plasma protein binding >97.3%). Compounds 2a
and 2b were profiled in vivo in the non-transgenic mouse model
and demonstrated a robust decrease of both plasma and brain Ab
levels with a dose of 10 mg/kg as shown in Table 2.20
F
O
H
R
O
F
S
N
H
O S O
O
CF3
Compda
R
Membraneb
Cell Ab40
IC50 (nM)
Cell Ab42
IC50 (nM)
IC50 (nM)
8
2a
–H
–CH3
30
1.6
na
1
na
0.5
2b
2d
2e
1.9
5.5
7.7
5
3
7
2
1
2
Table 2
Profile of 2a and 2b
F
O
H
R
2f
9.0
7.8
na
8.0
na
O
O
2g
14.6
F
S
N
H
O
O S
O
2h
60.9
na
na
Ph
OH
11
48.3
930
1198
O
O
2a; R = Me
CF3 2b; R = Et
NH2
12
13
14
na
9.5
17
na
4
Parameters
R = CH3 (2a)
R = C2H5 (2b)
3.8
40.6
4.9
64
OH
Membrane IC50 (nM)
1.6
1.9
5.0
2.0
40
<10
1
>30
10
Whole cell Ab40 IC50 (nM)
Whole cell Ab42 IC50 (nM)
Rat PK, (10 mg/kg), AUC (ng h/mL)19
Brain concn @ 6 h (ng/g)
Brain/plasma
1.0
0.5
139
<10
na
O
N
OH
O
16a
16b
45.5
48.4
na
na
na
na
CYP (3A4, 2D6 and 2C9) mM
hERG (rubidium efflux) % @ 5
h-Hepatocycte clearance (
Plasma protein binding
>30
4
lg/mL
l
L/min/M cells)
0.4
0.3
N
97.3
72 (pl); 57
(br)
98.1
84 (pl); 42
(br)
NonTG mouse % reduction of Ab40a @ 10
mpk/po20
na = not available.
a
Only compounds 8, 2a and 2b are (À) enantiomers, all others are racemic.
a
b
Mean values (n = 5). Expressed as a percent relative to vehicle controls.
Mean values (n = 2) SEM.

3648
T. K. Sasikumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3645–3648
12. Davis, F. A.; Reddy, R. E.; Kasu, P. V. N.; Portonova, P. S.; Carroll, P. J. J. Org. Chem.
In conclusion, we have discovered potent tetracyclic sulfone
-secretase inhibitors that are useful for reducing Ab production
in vivo. Compounds such as 2a and 2b showed excellent in vitro
and in vivo properties. Details of further SAR studies of these tetra-
cyclic c-secretase inhibitors as well as broad biological testing will
1997, 62, 3625.
c
13. Morris, J.; Wishka, D. G. J. Org. Chem. 1991, 56, 3549.
14. Data for compound 2b: 1H NMR (CDCl3 400 MHz) d 7.85 (d, 2H), 7.82 (d, 2H),
7.12 (m, 1H), 6.48 (m, 1H), 5.25 (d, 1H), 4.49 (d, 1H), 4.44 (d, 1H), 3.72 (br s,
1H), 3.13 (d, 1H), 2.46 (d, 1H), 2.29 (m, 1H), 2.12 (m, 1H), 1.97 (m, 1H), 1.78 (m,
1H), 1.53 (m, 5H), 1.16 (t, 3H).
be reported in subsequent publications.
F
nOe
F
O
H
H
Acknowledgments
2
3
H
O
4
7
5
8
We thank John Hunter for support of this project; Teresa Andre-
ani, Mark Liang, Tao Meng, Jianshe Kong and Jesse Wong for scaling
up of intermediates; T.M. Chan and Mary Senior for determining
stereochemistry of the compounds via NMR studies.
6
O
F
S
F
N
H
O S O
O
S
O
O
H
HN
S
O
O
References and notes
CF3
F
F
F
J = 14.1 Hz (H3 and H5; trans)
J = 3.5 Hz (H5 and H6; cis)
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