Design, synthesis, and structure-activity relationship studies of N-arylsulfonyl morpholines as γ-secretase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.09.028

Design and synthesis of cis-2,6-disubstituted N-arylsulfonyl morpholines as novel γ-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. Several different small alkyl groups are installed on the left-hand side to lower the CYP3A4 liability while maintaining excellent in vitro potency.

Full text of DOI:10.1016/j.bmcl.2010.09.028

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6606–6609
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, and structure–activity relationship studies of N-arylsulfonyl
morpholines as c-secretase inhibitors
Hongmei Li a, , Ruo Xu a, , David Cole a, John W. Clader a, William J. Greenlee a,
⇑
⇑
Amin A. Nomeir b, Lixin Song c, Lili Zhang c
a Department of Chemical Research, Merck Research Lab., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
b Department of Drug Safety and Metabolism, Merck Research Lab., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
c Department of Neurobiology, Merck Research Lab., 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:
Received 15 July 2010
Revised 2 September 2010
Accepted 7 September 2010
Available online 16 September 2010
Design and synthesis of cis-2,6-disubstituted N-arylsulfonyl morpholines as novel c-secretase inhibitors
for the potential treatment of Alzheimer’s disease (AD) is reported. Several different small alkyl groups
are installed on the left-hand side to lower the CYP3A4 liability while maintaining excellent in vitro
potency.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
c
-Secretase inhibitors
Alzheimer’s disease
Alzheimer’s disease (AD) is the most common form of neurode-
generative disease characterized by cognitive and memory deteri-
oration, and impairment of language and other daily activities. It is
estimated that about 5 million Americans currently suffer from
this disease, and an additional 360,000 people are newly diagnosed
every year.1 Due to its enormous burden on patients and the
healthcare system, research on the treatment of AD has drawn
tremendous attention from both academia and industry. At the
moment, one of the major hypotheses to explain the etiology of
AD is a chronic imbalance between b-amyloid peptide (Ab) produc-
tion and clearance, which results in the extracellular accumulation
of Ab. An excess of extracellular Ab results in the aggregation of Ab
into oligomers and plaques in the brain, which leads to neurode-
generation, dementia, and ultimately death. The formation of Ab
is the result of sequential cleavage of the b-amyloid precursor pro-
,4,6-trisubstituted piperidine sulfonamides, the 4-OH substitution
on the piperidine ring was brought into the ring to generate the
morpholine core (8b) (Fig. 1). Previous work on the morpholine
core focused on 5-aryl and 5-cyclopropyl substituted compounds
and showed that they have reduced CYP3A4 inhibition relative to
the corresponding piperidines.6
In addition, previous studies on the piperidine series have shown
that low molecular weight alkyl groups can replace the aryl or
cycloproyl group and retain good c
-secretase inhibition.4 Herein,
we report additional SAR studies on this morpholine sulfonamide
core. Small alkyl groups such as isopropyl, t-butyl, 1-methylcyclo-
propyl and cyclopropylmethyl were installed separately on the
left-hand side at C-5 position, then the right-hand side groups were
varied systematically.
First, the isopropyl group was introduced on the left-hand side
as shown in Scheme 1. D-Valinol was reacted with allyl bromide,
tein (APP) by two proteases, b-secretase (BACE) and
Thus both b- and -secretase are proposed as effective targets for
treatment of AD because of their central role in the production of
c
-secretase.2
c
followed by reaction with di-tert-butyl dicarbonate in dichloro-
methane (DCM) to provide compound 3.7 After dihydroxylation
of the allyl group,8 selective protection of the primary alcohol with
TBDPSCl and oxidation of the secondary alcohol with Dess–Martin
periodinane in DCM afforded ketone 4. Compound 4 was treated
with TFA to free the amine, and the in situ formed imine was
reduced with NaBH(OAc)3 to afford cis-morpholine 5 exclusively.
Morpholine 5 was reacted with 4-chlorobenzenesulfonyl chloride
in a mixture of pyridine/DCM, followed by deprotection with TBAF
in THF, oxidation of the alcohol to acid with NaIO4 and RuCl3ÁnH2O,
and methylation of the acid to give methyl ester 6. Methyl ester 6
was converted to the cyclopropyl alcohol using the Kulinkovich
reaction,9 and the alcohol was treated with COCl2 in DCM to
Ab peptide. To date, several series of
c-secretase inhibitors have
been reported.3
Previous reports from our laboratories showed that 2,6-disub-
stituted piperidine sulfonamides (1) are potent c-secretase inhibi-
tors.4 Installation of a 4-OH on the piperidine ring (2) effectively
reduced CYP3A4 inhibition seen in (1) while maintaining good
c
-secretase activity ( Fig. 1).5 To extend the SAR study of the
2-
⇑
Corresponding authors. Tel.: +1 908 740 6648 (H.L.), +1 908 740 3483 (R. X.).
E-mail addresses: hongmei.li@spcorp.com (H. Li), ruo.xu@spcorp.com (R. Xu).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.09.028

H. Li et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6606–6609
6607
OH
O
N
N
OH
O
N
O
N
OH
O
N
OH
N
SO2
N
SO2
N
O
O
SO2
O
2
1
8b
MembA 40 IC50 = 11.6 nM
β
Memb Aβ40 IC50 = 5.6 nM
CYP 3A4 IC50 = 19.5 μM
MembAβ40 IC50 = 18.9 nM
CYP 3A4 IC50 = 13.6 μM
Cl
CYP3A4 IC50 = 0.4 μM
Cl
Cl
Figure 1. Introduction of 4-OH on piperidine ring to reduce CYP3A4 inhibition.
O
O
O
O
OH
f, g
a, b
c, d, e
OTBDPS
N
H
NHBoc
NHBoc
NH2
OTBDPS
R1
3
4
5
O
O
O
OCH3
O
N
O
Cl
n
N
SO2
N
SO2
R2
N
SO2
l, m
h, i, j, k
O
O
O
6
8
7
Cl
Cl
Cl
Scheme 1. Reagents and conditions: (a) NaH, allyl bromide, THF; (b) di-tert-butyl dicarbonate, DCM, 58% for two-steps; (c) NMO, OsO4, t-BuOH/THF/H2O (10/3/1); (d)
TBDPSCl, imidazole, DMF, 70% for two-steps; (e) Dess–Martin periodinane, pyr., DCM, 57%; (f) TFA, DCM, 0 °C; (g) NaBH(OAc)3, DCM, 0 °C, 57% for two-steps; (h) 4-
chlorobenzenesulfonyl chloride, DMAP, pyr., 74%; (i) TBAF, THF; (j) NaIO4, RuCl3ÁnH2O, EtOAc/CH3CN/H2O (1/1/2), 95% for two-steps; (k) TMSCHN2, toluene/CH3OH (4/1), 75%;
(l) Ti(OiPr)4, EtMgBr, THF, 0 °C, 85%; (m) COCl2, pyr., DCM, 73%; (n) amine, DCM.
bition, although they have good rat AUC values. On the other hand,
provide carbonochloridate 7. By reacting with selected amines, car-
bamates 8 were obtained.
As shown in Table 1, this series of compounds has good in vitro
activity in general. The compounds with free basic amines on the
right-hand side (8a, 8e, and 8f) still have undesirable CYP3A4 inhi-
the compounds without basic amines on the right-hand side (8b,
8c, and 8d) have a much better CYP3A4 inhibition profile. Unfortu-
nately, these compounds also have low rat AUC values.
Next, we introduced t-butyl and 1-methylcyclopropyl as the
left-hand side chain. Both groups were introduced by use of a similar
procedure as shown in Scheme 2. The condensation of N-Boc-O-ben-
zyl-L-serine with 1-bromopinacolone provided compound 9. This
compound was then reacted with TFA in DCM to give free amine,
the in situ generated imine was reduced with NaBH(OAc)3 to afford
the morpholinone core, which was reacted with 4-chlorobenzene-
sulfonyl chloride to give 10. Morpholinone 10 was reduced to the
diol, followed by intramolecular Mitsunobu reaction to close the
morpholine ring and hydrogenation to provide alcohol 11. Due to
the steric hindrance from the left-hand side, the attempted conver-
sion of the primary alcohol 11 to a cyclopropyl alcohol through the
formation of an ester followed by the Kulinkovich reaction as shown
in Scheme 1 was not successful here. Therefore, the primary alcohol
was treated with 4-nitrophenyl chloroformate and pyridine in THF/
CH3CN directly, followed by reacting with different amines to
provide the carbonates. The biological results for those compounds
are shown in Table 2. Due to the absence of cyclopropyl on the
right-hand side, the in vitro activities for this series of compounds
decreased as expected.5 However, the CYP3A4 inhibition data for
these compounds suggested that the t-butyl group on the left-hand
side could help to improve the CYP3A4 profile compared to
1-methylcyclopropyl.
Table 1
Structure–activity relationship of 5-isopropylmorpholine series
O
R1
R2
O
N
N
SO2
O
Cl
d
Compounda
NR1R2
Membr Ab40
IC50 (nM)
CYP3A4c
(nM)
Rat AUC0–6 h
(h nM h)
b
N
8a
8b
8c
2.0
18.9
6.5
0.5
13.6
13.8
4970
36
NH
OH
N
N
0
OH
8d
8e
8f
17.0
9.3
30.0
6.4
0
1120
3928
N
N
N
OH
NH
A cyclopropylmethyl group was also introduced as the left-hand
side group on the morpholine core. Allylation of Boc-D-serine
14.5
0.3
NH
methyl ester provided allyl ether 13,10 followed by ozonolysis of
the alkene and capture of the iminium cation with methanol to
give morpholine 14. This was reacted with allytrimethylsilane in
the presence of BF3ÁEt2O to introduce the cis-allyl group on the
left-hand side.11 After reacting with 4 N HCl in dioxane, treatment
with 4-chlorobenzenesulfonyl chloride in a mixture of pyridine
a
All compounds are pure enantiomers.
Data for inhibition of Ab40 were measured by use of a membrane-based
-secretase, and values are the mean of two experiments.
Values are determined after 30 min pre-incubation with compound.
Measured over 0–6 h after 10 mg/kg oral dosing in rat.
b
preparation of
c
c
d

6608
H. Li et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6606–6609
O
O
N
O
O
O
OH
OBn
e, f, g
b, c, d
O
O
a
N
SO2 OH
SO2 OBn
OBn
BocHN
BocHN
9
10
11
O
R1
N
Cl
Cl
O
N
R2
SO2
O
h, i
12
Cl
Scheme 2. Reagents and conditions: (a) 1-bromopinacolone, KOH, KI, CH3OH/DCM (2/1), 92%; (b) TFA, DCM; (c) NaBH(OAc)3, DCM, 54% for two-steps; (d) 4-
chlorobenzenesulfonyl chloride, DMAP, pyr.; (e) NaBH4, CaCl2, THF/EtOH, 60 °C, 29% for two-steps; (f) DIAD, PPh3, toluene, 60 °C, 84%; (g) H2, PtO2, EtOH; (h) 4-nitrophenyl
chloroformate, pyr., THF/CH3CN (1/1), 67% for two-steps; (i) amine, DCM.
Table 3
Structure–activity relationship of 5-cyclopropylmethyl morpholine series
Table 2
Structure–activity relationship of 5-t-butylmorpholine series
O
R1
R2
O
N
R1
O
N
SO2
O
O
N
R
N
SO2
R2
O
Cl
Compounda NR1R2
Membr
Ap40 IC50
(nM)
CYP3A4c RatAUC0–6 h
d
Cl
b
(nM)
(h nM h)
Compounda
R
NR1R2
Membr Ab140
IC50 (nM)
CYP3A4c
(nM)
b
N
N
N
N
18a
18b
18c
18d
18e
0.8
0.9
4.4
5.5
3.6
0.8
2.3
4584
1283
13
NH
N
N
N
N
N
12a
12b
34.7
23.8
7.1
OH
OH
OH
OH
107.9
O
>30
>30
3.2
12c
12d
12e
131.1
20.4
5.5
1.5
0.5
N
N
O
N
N
N
60
NEt
N
39.3
OH
1348
N
N
OH
OH
a
All compounds are pure enantiomers.
Data for inhibition of Ab40 were measured by use of a membrane-based
-secretase, and values are the mean of two experiments.
b
N
N
preparation of
c
18f
11.6
5.7
2.0
1.4
1225
1021
c
Values are determined after 30 min pre-incubation with compound.
N
N
18g
O
N
and DCM gave N-arylsulfonyl morpholine 15. After cyclopropana-
tion of the olefin and Kulinkovich reaction of the methyl ester,9
cyclopropyl alcohol 17 was prepared. Again, this was converted
to chlorocarbamate and reacted with amines to give carbamates
18 (Scheme 3). It should be noted that all final compounds were
pure enantiomers and the compounds with this absolute configu-
ration were more active as determined previously.4b
O
18h
18i
29.3
27.6
>30.0
>30
N.D.
77
N
OH
N
N
N
Extensive SAR studies on the right-hand side were carried out in
this series, and the biological data for selected compounds was
shown in Table 3. In general, the compounds with high CYP3A4
inhibition have high rat AUC values, and the ones with low CYP3A4
inhibition have low rat AUC values. Compared to the previous two
series and the series with cyclopropyl or aryl substitution at C-5 on
the left-hand side,6 the cyclopropylmethyl substitution provided
the best in vitro activity and compatible CYP profile. Compound
18j has the best balance of good Ab40 inhibition (3.1 nM) with rea-
sonably good rat PK and acceptable CYP3A4 inhibition.
18j
18k
18l
3.1
2.6
7.4
11.3
30.0
>30
1343
894
37
N
H
N
N
N
O
N
H
a
All compounds are pure enantiomers.
Data for inhibition of Ab40 were measured by use of a membrane-based
-secretase, and values are the mean of two experiments.
Values are determined after 30 min pre-incubation with compound.
Measured over 0–6 h after 10 mg/kg oral dosing in rat.
b
preparation of
c
In summary, the proper combination of small alkyl groups on
the left-hand side and amines on the right-hand side could provide
c
d

H. Li et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6606–6609
6609
O
O
N
SO2
CO2CH3
HO
O
b, c
a
d, e,f
H3CO
N
CO2CH3
BocHN
CO2CH3
BocHN
CO2CH3
Boc
14
13
15
O
O
R1
N
O
N
Cl
O
OCH3
O
OH
N
SO2
R2
N
SO2
O
i, j
g
SO2
h
16
17
18
Cl
Cl
Cl
Scheme 3. Reagents and conditions: (a) carbonic acid allyl ethyl ester, [AllylPdCl]2, PPh3, THF, 70%; (b) O3, SMe2, CH3OH; (c) CH3OH, TsOH, 91% for two-steps; (d)
allyltrimethylsilane, BF3ÁOEt2, DCM, 48%; (e) 4 N HCl in dioxane; (f) 4-chlorobenzenesulfonyl chloride, pyr., 74% for two-steps; (g) ZnEt2, TFA, CH2I2, THF, 87%; (h) Ti(O-iPr)4,
EtMgBr, THF, 50%; (i) COCl2, pry., DCM, 78; (j) amine, DCM.
4. (a) Asberom, T.; Bara, T. A.; Clader, J. W.; Greenlee, W. J.; Guzik, H. S.; Josien, H.
B.; Li, W.; Parker, E. M.; Pissarnitski, D. A.; Song, L.; Zhang, L.; Zhao, Z. Bioorg.
compounds with good in vitro activity and reduced CYP3A4
inhibition.
Med. Chem. Lett. 2007, 17, 205; (b) Pissarnitski, D. A.; Asberom, T.; Bara, T. A.;
Buevich, A. V.; Clader, J. W.; Greenlee, W. J.; Guzik, H. S.; Josien, H. B.; Li, W.;
McEwan, M.; McKittrick, B. A.; Nechuta, T. L.; Parker, E. M.; Sinning, L.; Smith, E.
M.; Song, L.; Vaccaro, H. A.; Voigt, J. H.; Zhang, L.; Zhang, Q.; Zhao, Z. Bioorg.
Med. Chem. Lett. 2007, 17, 57; (c) Asberom, T.; Zhao, Z.; Bara, T. A.; Clader, J. W.;
Greenlee, W. J.; Hyde, L. A.; Josien, H. B.; Li, W.; McPhail, A. T.; Nomeir, A. A.;
Parker, E. M.; Rajagopalan, M.; Song, L.; Wong, G. T.; Zhang, L.; Zhang, Q.;
Pissarnitski, D. A. Bioorg. Med. Chem. Lett. 2007, 17, 511; (d) McBriar, M. D.;
Clader, J. W.; Chu, I.; Del Veccjio, R. A.; Favreau, L.; Greenlee, W. J.; Hyde, L. A.;
Nomeir, A. A.; Parker, E. M.; Pissarnitski, D. A.; Song, L.; Zhang, L.; Zhao, Z.
Bioorg. Med. Chem. Lett. 2008, 18, 215.
Acknowledgment
We sincerely thank Drs. Andy Evans, T.-M. Chan, Alexis Buevich
and Ms. Rebecca Osterman for NMR analysis.
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