Isopropyl amide derivatives of potent and selective muscarinic M 2 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2004.01.033

Low molecular weight amide derivatives were synthesized and evaluated as M₂ receptor antagonists for the treatment of Alzheimer's disease. Isopropyl amides 19 and 31 are highly potent, selective and low molecular weight M₂ receptor a

Full text of DOI:10.1016/j.bmcl.2004.01.033

Bioorganic& Medicinal Chemistry Letters 14 (2004) 1791–1794
Isopropyl amide derivatives of potent and selective muscarinic
M2 receptor antagonists
Anandan Palani,* Sundeep Dugar, John W. Clader, William J. Greenlee, Vilma Ruperto,
Ruth A. Duffy and Jean E. Lachowicz
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Received 3 September 2003; accepted 6 January 2004
Abstract—Low molecular weight amide derivatives were synthesized and evaluated as M2 receptor antagonists for the treatment of
Alzheimer’s disease. Isopropyl amides 19 and 31 are highly potent, selective and low molecular weight M2 receptor antagonists with
structural features different from our clinical candidate 1.
# 2004 Elsevier Ltd. All rights reserved.
Alzheimers’s disease (AD) is a neurodegenerative dis-
ease characterized by a progressive loss of cognitive
function which leads to severe memory loss accom-
panied by behavioral changes. Current treatment for
AD involves increasing acetylcholine (ACh) levels in the
synapse through administration of acetylcholinesterase
inhibitors.1 An alternate method which we are pursuing
is to enhance acetylcholine levels through antagonism of
ism would negate the therapeutic effects of increased
ACh levels, and blockade of other muscarinic receptors
would increase the potential for unwanted side effects.
Recently, co-workers from our laboratories have dis-
closed low molecular weight sulfoxide analogues 2 and
(+)-3 derived from our clinical candidate 1. Compound
(+)-3 showed oral efficacy in animal models compar-
able to that of 1.2b,4 We report here the identification of
isopropyl amides 19 and 31 as potent and selective M2
receptor antagonist which possess structural features
different from those of 2 and 3 (Fig. 1).
presynapticM muscarinic receptors.2,3 Selective bind-
2
ing to the M2 receptor over other muscarinic subtypes is
an important criteria for the program, as M1 antagon-
Figure 1. M2 receptor antagonists.
* Corresponding author. Tel.:+1-908-740-7158. fax: +1-908-740-7305; e-mail: anandan.palani@spcorp.com
0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.01.033

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A. Palani et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1791–1794
Scheme 1. (a) TFAA, CF3SO3H, 1,3-dibromo-5,5-dimethylhydantoin, CH2Cl2, 50–60%; (b) K2CO3, MeOH, 98%; (c) NaBH(AcO)3, 1,2-DCE, 1-t-
butoxycarbonyl-4-piperidone, 60%; (d) n-BuLi, RNCO, THF, 70–90%; (e) TFA, CH2Cl2, 90%; (f) ArCOOH, EDCI, DMAP, CH2Cl2, 85–95%.
Scheme 2. (a) NaBH(AcO)3, 1,2-DCE, 1-t-butoxycarbonyl-4-piperidone, 50%; (b) n-BuLi, iPrNCO, THF, 71%; (c) TFA, CH2Cl2, 90%; (d)
ArCOOH, EDCI, DMAP, CH2Cl2, 85–95%.
Table 1. Effect of left hand amide modifications on receptor binding and selectivity
Compd
R
Ar
—
M2 Ki (nM)
M1/M2
734
M3/M2
787
M4/M2
69
M5/M2
95
1
—
0.89
2
iPrSO2
—
17
21
101
77
na
170
6.6
na
22
12
na
36
48
(+)-3
8
—
0.89
2.1
iPrNHCO
9
iPrNHCO
tBuNHCO
tBuNHCO
c-hexylNHCO
c-hexylNHCO
PhNHCO
7
18
121
72
12
1
na
1.6
10
na
na
na
na
na
na
5
na
na
14
na
na
na
na
10
11
12
13
14
106
1300
15
na
na
na
na
31
9
104
122
15
PhNHCO
5
na, not available.

A. Palani et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1791–1794
1793
Synthesis of the amide targets is outlined in Scheme 1.
Selective bromination of commercially available 4-ben-
zyl piperidine afforded p-bromobenzyl piperidine tri-
fluoroactamide which upon hydrolysis afforded 5.
Reductive amination of 5 with 1-tert-butoxycarbonyl-4-
piperidone provided piperidinyl piperidine 6. The
amides 7 were prepared by Br–Li exchange followed by
reaction with the commercially available isocyanates.
The final products 8–26 were obtained after deprotec-
tion followed by aryl amide formation with appropriate
aromatic acids under standard conditions. The synth-
eses of the ketal targets are outlined in Scheme 2. Com-
pound 27, prepared according to a previously described
procedure was converted to final targets 30–35 in a
manner similar to non-ketal derivatives.5
Table 2. Effects of aryl amide modifications on receptor binding and
selectivity
Compd
Ar
M2 Ki
(nM)
M1/M2 M3/M2 M4/M2 M5/M2
8
2.1
5
77
113
72
7
6.6
12
14
na
na
7
48
19
16
17
18
19
20
21
22
23
24
25
26
97
The Ki values for receptor binding were determined
using cloned human muscarinic receptors as previously
described.6 The results shown in Table 1 highlight the
structure–activity relationships for left side amide
modifications. First, for our initial structure–activity
studies we fixed the right side aryl amide as either 4-
fluoronaphthamide or o-toluamide based on our pre-
vious studies, which are optimal for providing good M2
biding affinity and selectivity.7
9
na
na
382
na
na
na
na
54
na
na
164
na
na
na
na
58
40
1.6
27
5
107
7
na
na
na
na
10
na
na
In general, M2 affinity was sensitive to both terminal
amide modifications. Isopropyl amides 8 and 9 were
identified to be the best in terms M2 potency and selec-
tivity. 4-Fluoronaphthyl aromaticamides gave us good
M2 selective antagonists with exception of compounds
12 and 14. Compound 9 containing o-toluamide pro-
vided a high degree of selectivity for M2 versus M1, but
however for other compounds, this modification resul-
ted in non selective and less active antagonists.
60
51
12
62
40
201
6
78
12
9
Having established the left hand isopropyl amide as a
suitable amide, we then investigated diverse substitution
patterns on the right side aromaticregion. Representa-
tive examples are shown in Table 2. The difluorinated
naphthyl compound 16 showed good selectivity for M2
versus M1 and M3, but with 2-fold loss of M2 affinity as
compared to 8. Compound 18 is the best among the
several quinoline derivatives which were studied as a
potential replacement for the naphthyl ring. The indole
heterocyclic amide derivative 19 showed excellent M2
receptor binding affinity and selectivity versus other
subtypes except M4. Earlier results have suggested that
introducing polar 2-amino-3-methylphenyl group can
be advantageous for improving not only potency and
selectivity but also in vivo activity.2b However, in this
series, introduction of 2-amino-3-methyl phenyl group
gave low M2 affinity and poor selectivity (25). The 3-
amino-2-methyl phenyl group as in 26 was found to be
excellent and showed a high level of selectivity and
potency. From these SAR investigations, we identified
compounds 19 and 26 with desired binding and selec-
tivity profile for further investigation.
na
na
na
na
1.6
na, not available.
containing ketals at the benzylic position. The target
compounds were prepared using approaches similar to
those in Scheme 1, starting from isonipecotic acid as
shown in Scheme 2. As expected, ketal analogues 30 and
34 showed excellent affinity and 2- to 3-fold improve-
ment in selectivity relative to 8 and 19. Surprisingly, 2-
amino-3-methyl group which was found to be less
favorable in the earlier series demonstrated excellent M2
binding affinity and selectivity in the ketal series. Note
that the introduction of double bond at the benzylic
position similar to 3 in the isopropyl amide series resul-
ted in potent and non-selective muscarinic antagonists
antagonists (Table 3).
Earlier studies have shown that replacement of the
benzylicmethylene unit with a ketal oculd improve
In summary, we have identified structurally new, selec-
tive and high affinity M2 receptor ligands by manipu-
lation of the substitution pattern on the two amide
metabolicstability, M receptor affinity and selectivity.8
Therefore we investigated a panel of isopropyl amides
2

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A. Palani et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1791–1794
Table 3. Effects of aryl amide modifications on receptor binding and
selectivity in the benzylidene ketal series
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Compd
Ar
M2 Ki
(nM)
M1/M2 M3/M2 M4/M2 M5/M2
30
31
32
33
34
35
2.4
1.1
9
214
120
49
116
259
na
19
22
na
na
42
na
84
234
na
35
28
na
na
2.7
1.9
364
60
222
na
25
na
na, not available.
moieties of the target molecule, along with ketal modi-
fication. Compounds 19 and 31 with >100-fold selec-
tivity for the M2 receptor, relative to M1, M3 and M5
were obtained, particularly with a combination of iso-
propyl amide and indole aryl amide. Further develop-
ment of these leads will be reported in due course.
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Acknowledgements
We thank Dr. Ashit Ganguly and Dr. Catherine Strader
for helpful discussions, support and encouragement. We
also thank Dr. Pradip Das for obtaining analytical data.