A-ring modification of SCH 900229 and related chromene sulfone γ-secretase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.11.054

Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH 900229) using electrophilic Selectfluor led to an unexpected oxidation of the A-ring to give difluoroquinone analog 1a. Oxidation of other related chromene γ-secretase inhibitors 2-8 resulted in similar difluoroquinone analogs 2a-8a, respectively. These quinone products exhibited comparable in vitro potency in a γ-scretase membrane assay, but were several fold less potent in a cell-based assay in lowering Aβ40-42, compared to their parent compounds.

Full text of DOI:10.1016/j.bmcl.2012.11.054

Bioorganic & Medicinal Chemistry Letters 23 (2013) 850–853
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A-ring modification of SCH 900229 and related chromene sulfone
c-secretase inhibitors
⇑
Wen-Lian Wu , Thavalakulamgara K. Sasikumar, Martin S. Domalski, Li Qiang, Duane A. Burnett,
John Clader, William J. Greenlee, Tze-Ming Chan, Julie Lee, Lili Zhang
Merck Research Laboratories, 2015 Galloping Hill Rd, 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:
Available online 28 November 2012
Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH
900229) using electrophilic Selectfluor™ led to an unexpected oxidation of the A-ring to give difluoroqui-
none analog 1a. Oxidation of other related chromene
oroquinone analogs 2a–8a, respectively. These quinone products exhibited comparable in vitro potency
in a -scretase membrane assay, but were several fold less potent in a cell-based assay in lowering Ab40–
42, compared to their parent compounds.
c-secretase inhibitors 2–8 resulted in similar diflu-
Keywords:
Alzheimer’s disease
c
c
-Secretase inhibitor
SCH 900229
Difluoroquinone
Ó 2012 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD) is a progressive and devastating neu-
rodegenerative disorder affecting millions of people. AD is the
most severe form of dementia and the fourth major cause of death
in the developed world. Currently there are no disease-modifying
medications to slow down the progression of AD; the only thera-
pies are palliative treatments of modest efficacy.1 Amyloid plaques
consisting of 40–42 amino acid b-amyloid peptides (Ab) and neu-
rofibrillary tangles are the two pathological hallmarks observed
in AD patients brains. Accumulation of Ab has been proposed to
be responsible for neuronal toxicity that is associated with AD.2,3
Ab peptides are generated from a larger amyloid precursor protein
(APP) by two sequential cleavages, first by b-site APP cleaving en-
to potentially reduce metabolism of this relatively electron-rich
site. In a rat pharmacokinetic and metabolism study (data not
shown), an A-ring oxidation metabolite (M+16), presumably the
C9-hydroxylated analog of 1, was indeed observed. Owing to the
linear synthesis of compound 1,7 the option of functionalization
of the A-ring at a late stage was limited. Initially, as illustrated in
Scheme 1, when compound 1 was treated with N-iodosuccinimide
in the presence of trifluoroacetic acid, as expected compound 9
was obtained in good yield.12 However, its potency dropped dra-
matically (Ab40 membrane IC50 of 1276 nM) compared to com-
pound 1. This result indicated limited tolerance for steric bulk at
this position.
Fluorine has been used widely in medicinal chemistry as an
isosteric replacement for hydrogen, based on their similar sizes.
Selectfluor™ is a well-known reagent for electrophilic fluorination
of organic compounds, and thus was chosen for the introduction of
9-fluoro on the A-ring of compound 1.13 Thus, a solution of com-
pound 1 and an excess amount of Selectfluor™ in acetonitrile
was stirred at room temperature for 3 h. No reaction was detected
by TLC and LC–MS. The solution was then heated at 80 °C overnight
(20 h), and under those conditions, starting material 1 was com-
pletely consumed as judged by LC–MS, although no desired 9-flu-
oro-substituted product was detected. Instead, compound 1a was
isolated as the major product (Scheme 1). When compound 2
was subjected to the same reaction conditions, a similar analog
2a was obtained (Scheme 2). Extensive analysis of 2a employing
various NMR techniques, including HSQC, COSY, and HMBC, con-
firmed its structure to be the oxidation product.14 This result came
as a surprise to us, considering the two electron-poor sites (with F-
attached) were oxidized further while the electron-rich 9-position
remained intact.
zyme (BACE1) and then by
els by inhibition of BACE1 or
represent a promising approach to develop disease-modifying
treatments for AD. Indeed, many small molecule BACE1 and
c
-secretase.4 Thus, reduction of Ab lev-
-secretase should, in theory,
c
c
-
secretase inhibitors have been pursued as potential treatments
for AD in the last decade.5
Towards this end, we have successfully identified and devel-
oped a novel series of bis-pyran sulfone c-secretase inhibitors. In
previous communications, we have disclosed the discovery of our
clinical compound SCH 900229 (1, Fig. 1)6 and also described a de-
tailed SAR study of the two sulfone side chains of that molecule.7
Herein, SAR investigation on the A-ring of compound 1 and struc-
turally related analogs 2–8 (Fig. 1) are reported.8–11
As part of our program to continue SAR investigations around
the c-secretase inhibitor 1, we were interested in the incorporation
of small groups at the 9-position of the A-ring, preferably fluorine,
⇑
Corresponding author. Tel.: +1 732 594 2987; fax: +1 732 594 3007.
E-mail address: wen-lian.wu@merck.com (W.-L. Wu).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.11.054

W.-L. Wu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 850–853
851
F
A
F
A
F
F
F
6
O
O
O
O
O
O
O
5
8
9
O
S
O
O
S
O
O O
S
H
H
O
H
O
H
+
F
X
Y
SelectfluorTM
F
O
O
F
O
F
O
S
X
3
S
S
S
O
O
2
CF3
CF3
CF3
4X = CH2CH2SO2Me, Y = H
5X = CH2NHSO2CF3, Y = H
6X = H, Y = CH2NHSO2Pr-c
1 X = Cl (SCH 900229)
2 X = CF3
3 X = CN
2
F
F
F F
O
O
O
S
O
O O
S
F
H
O
H
O
O
O
OH-
or
-HF
A
H
HO
F
O
O
S
S
O
O
O
+ H2O- H+
F
O
S
O
O
S
X
N
H
CF3
CF3
2a
7 X = CF3
8 X = CN
Scheme 2. Plausible reaction mechanism.
Figure 1.
c
-Secretase inhibitors.
electrophilic hydroxyfluorination likely involves a 1,4-addition of
HOF to the A-ring to generate an unstable intermediate that
decomposes to the stable difluoroquinone 2a. The required HOF
species is known to be formed from Selectfluor™ in combination
with water present in the reaction system.17
F
O
O
O
O
H
O
A series of other related tricyclic and tetracyclic
c-secretase
S
inhibitors 3–8 were subsequently treated with Selecfluor™ under
the same conditions. Not surprisingly, all gave the corresponding
difluoroquinone structures 3a–8a. The yields for this transforma-
tion were modest, and no efforts were made to optimize the reac-
tion conditions to achieve higher yields.
F
O
S
1 SCH 900229
IC50 = 1.3 nM
Cl
Interestingly, when compound 1a was tested in the membrane
assay for Ab40 lowering, it displayed potency similar to that of par-
ent compound 1.18 As revealed in Table 1, similar trends existed
with other pairs, such as 5/5a, 7/7a, and 8/8a. Compounds 2a, 3a,
4a and 6a were even several-fold more potent than their corre-
sponding parents 2, 3, 4, and 6. However, in the cell-based assay,19
all the difluoroquinone analogs 1a–8a exhibited much less potency
in lowering both Ab40 and Ab42 than their parent compounds 1–8.
The reason for the shift between the membrane and cell potency
for these difluoroquinone analogs remains unclear; the cell shift
could be related to the reduced ClogP values of the difluoroqui-
none structures. For example, ClogP for compound 1 is 2.58
whereas ClogP for compound 1a is 1.35, which may fall outside
the optimal range for cell activity.
a
b
F
F
F
O
H
O
O
O
S
O
O O
S
H
O
I
F
O
O
S
O
O
S
O
Cl
Cl
1a
9
In summary, treatment of c-secretase inhibitor SCH 900229 (1)
Scheme 1. Reagents and conditions. (a) NIS, CF3COOH, room temperature; (b)
Selectfluor™, MeCN, 80 °C.
with SelectfluorTM led to identification of an unusual modification
of the A-ring. These difluoroquinone analogs have similar in vitro
potency in Ab reduction as their precursor difluorophenyl com-
pounds but are less potent in the cell based assay. This result sug-
gests other possibilities for A-ring replacement of compound 1,
such as non-polar, non-aromatic moieties.
A survey of the literature provided several precedents regarding
this unusual type of reaction. For example, pentafluorophenylio-
dine tetrafluoride was oxidized by XeF2–H2O to give oxygen-con-
taining
perfluorocyclohexadiene-1-yliodine
tetrafluorides;15
treatment of 2-methoxynaphthalene and 2,5-diarylfurans with
Selectfluor™ gave 1,1-difluo-2-oxo-1,2-dihydronaphthalene and
the ring-opening product cis-enediones, respectively.16,17 One
plausible mechanism is illustrated in Scheme 2. This so-called
Acknowledgment
The authors would like to thank Dr. Briendra Pramanik’s group
for analytical support.

852
W.-L. Wu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 850–853
Table 1
Biological data for modified A-ring analogsa
b,c
b,c
Compound
Structure
Ab40 IC50 (nM)
Ab42 IC50 (nM)
Membrane
1.3
Cell
4.0
Cell
1.0
1
F
F
O
O
O
S
O
H
O
O
1a
2
S
1.2
15
26
11
11
O
Cl
4.0
F
F
O
O
O
S
O
H
O
O
O
S
2a
3
1.8
66
56
25
27
CF3
O
9.0
F
F
O
S
O
H
O
O
O
3a
4
S
21
43
1600
63
410
21
O
CN
O
F
F
O
S
O
H
H
H
O
O
S
4a
1.9
54
130
73
49
32
O
CF3
O
5
F
F
O
O
S
N
CF3
H
O
O
S
5a
78
92
330
87
200
19
O
CF3
O
6
F
F
O
O
O
O
S
S
6a
6.8
280
110
N
O
H
CF3

W.-L. Wu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 850–853
853
Table 1 (continued)
b,c
b,c
Compound
Structure
Ab40 IC50 (nM)
Ab42 IC50 (nM)
7
1.9
5.0
2.0
F
F
O
O
H
O
S
O
S
7a
3.9
46
25
N
H
O
O
CF3
O
8
4.7
4.0
2.0
F
F
H
O
S
O
O
8a
3.5
110
31
S
N
H
O
O
CN
a
For compounds 1–8, see Refs. 6–11.
b
c
The IC50 data are an average of at least two measurements; the standard deviation was 20%.
Determined in HEKAwe-Lon 293 cells.
80 °C for 20 h. The solvent was evaporated; the residue was diluted with 40 mL
of water and extracted with two 50 mL portions of dichloromethane. The
combined organic extracts were concentrated, and the residue was purified by
reverse-phase HPLC (C18 column, 5–95% MeCN in water plus 1% HCOOH, over
20 min) to give 0.048 g (39%) of compound 2a. 1H NMR (500 MHz, CDCl3) d 7.9
(d, J = 8.4 Hz, 1H), 7.8 (d, J = 8.4 Hz, 1H), 6.73 (dt, J = 10.3, 5.3 Hz, 1H), 6.14 (d,
J = 10.3 Hz, 1H), 5.12 (dd, J = 12.8, 2.8 Hz, 1H), 4.64 (d, J = 12.8 Hz, 1H), 3.81
(ddd, J = 12.2, 4.2, 2.2 Hz, 1H), 3.30 (m, 1H), 3.29 (m, 1H), 3.07 (m, 1H), 3.02 (dt,
J = 1.6, 12.2 Hz, 1H), 2.93 (s, 3H), 2.88 (d, J = 13.2 Hz, 1H), 2.67 (dd, J = 10.4,
References and notes
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with installation of the sulfone side chain.
2.8 Hz, 1H), 2.44 (m, 1H), 2.07 (ddd, J = 13.2, 12.2, 4.2 Hz, 1H), 2.05 (m, 1H). 13
C
4
2
NMR (125 MHz, CDCl3)
d 182.6 (s, JCF = 3.0, 3.0 Hz), 163.3 (s, JCF = 24.4,
2 2
24.4 Hz), 140.3 (s), 135.9 (s, JCF = 33.1,33.1,33.1 Hz), 133.0 (d, JCF = 27.5,
3
3
27.5 Hz), 132.3 (d, JCF = 8.8, 8.8 Hz), 131.4 (d), 125.7 (d, JCF = 3.6, 3.6, 3.6 Hz),
123.1 (s, 1JCF = 273.0, 273.0, 273.0 Hz), 107.2 (s, 1JCF = 234.8, 237.7 Hz), 105.6 (s,
3JCF = 3.8, 3.8 Hz), 72.2 (d), 66.4 (t), 65.3 (s), 63.7 (t), 50.8 (t), 40.9 (q), 37.3 (d),
29.5 (t), 25.8 (t). 19F NMR (407 MHz, CDCl3)
d
À63.6 (s), À103.2 (dd,
3JHF = 5.3 Hz, JFF = 335 Hz), À104.1 (dd, JHF = 5.3 Hz, JFF = 335 Hz). LC–MS:
2
3
2
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14. Typical procedure: A mixture of 0.119 g (0.22 mmol) of compound 2 and 0.39 g
(1.1 mmol) of Selectfluor™ (air products) in 6 mL of acetonitrile was heated at