Novel indanyl-substituted imidazo[1,2-a]pyridines as potent reversible inhibitors of the gastric H+/K+-ATPase

Article abstract of DOI:10.1016/j.bmcl.2007.08.003

A series of novel 8-indanylamino- and 8-indanyloxy-substituted imidazo[1,2-a]pyridines with reduced lipophilicity was synthesized from easily accessible starting compounds. The anti-secretory activity of these compounds has been assessed in a competitive

Full text of DOI:10.1016/j.bmcl.2007.08.003

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5374–5378
Novel indanyl-substituted imidazo[1,2-a]pyridines as
potent reversible inhibitors of the gastric H+/K+-ATPaseq
Peter Jan Zimmermann,* Wilm Buhr, Christof Brehm, Andreas Marc Palmer,
Martin Philipp Feth, Jo¨rg Senn-Bilfinger and Wolfgang-Alexander Simon
Nycomed GmbH, Byk-Gulden-Str. 2, D-78467 Konstanz, Germany
Received 29 June 2007; revised 1 August 2007; accepted 2 August 2007
Available online 11 August 2007
Abstract—A series of novel 8-indanylamino- and 8-indanyloxy-substituted imidazo[1,2-a]pyridines with reduced lipophilicity was
synthesized from easily accessible starting compounds. The anti-secretory activity of these compounds has been assessed in a com-
petitive binding assay against H+/K+-ATPase from hog gastric mucosa. Some of the compounds proved to be potent inhibitors of
the gastric acid pump.
Ó 2007 Published by Elsevier Ltd.
The gastric H+/K+-ATPase located in the parietal cells is
responsible for the final step of acid secretion in the
stomach and is the main target in the pharmacological
treatment of acid related diseases. Since their introduc-
tion into the market, irreversible inhibitors of the H+/
K+-ATPase (proton pump inhibitors, PPIs) have revolu-
tionized the treatment of gastro-oesophageal reflux
disease (GERD).1 Despite of the clear success of these
agents, there are still limitations of current GERD ther-
apy with PPIs.2 The new reversible potassium competi-
tive acid blockers (P-CABs) may offer therapeutic
advantages over PPI therapy, and may have the poten-
tial to achieve faster inhibition of acid secretion and
longer duration of action compared to PPIs, resulting
in quicker symptom relief and healing.3
lism.9 As part of our studies on the development of
new P-CABs, we herein report the synthesis and bio-
logical evaluation of some related 8-indanylamino-
and 8-indanyloxy-substituted imidazo[1,2-a]pyridines
2 as well as certain derivatives thereof with significantly
reduced lipophilicity (Fig. 1).11
Recent experiments conducted in our laboratory have
demonstrated that various 8-amino- and 8-hydroxy-
imidazo[1,2-a]pyridines react with a wide range of
substituted 1,2-epoxyindanes under weakly basic
conditions to give the respective indanyl-substituted
imidazo[1,2-a]pyridines.12 In order to employ this ap-
proach for the synthesis of the target compounds 2 of
both N- and O-series, the appropriate precursor imi-
dazo[1,2-a]pyridines had to be prepared. The known
Most of the P-CABs disclosed so far belong to the
structural class of imidazo[1,2-a]pyridines.4–6 More re-
cently, a series of 8-(2,6-dialkylbenzylamino)-substi-
tuted imidazo[1,2-a]pyridines has been reported that
effectively inhibit gastric acid secretion by reversible
binding to the H+/K+-ATPase.7–10 However, many
compounds of this series, such as the known inhibitor
AR-HO47108 (1)8 (Fig. 1), suffer from high lipophilic-
ity and are therefore susceptible to extensive metabo-
O
O
H2N
N
R'
N
R
N
N
N
NH
X
OH
Keywords: H+/K+-ATPase; Imidazo[1,2-a]pyridine; Anti-ulcer; Gastric
acid inhibitor.
q
Design of novel P-CABs, I.
Corresponding author. Tel.: +49 (0) 7531 84 2087; fax: +49 (0) 7531
84 92087; e-mail: pjz@lycos.de
2, X = NH, O
Figure 1. Structure of P-CAB AR-HO47108 (1) and target compound 2.
AR-HO47108 (1)
*
0960-894X/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2007.08.003

P. J. Zimmermann et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5374–5378
5375
HOOC
MeOOC
Br
Br
N
N
i
ii
N
i
N
ii
OH
Cl
N
NH2
NO2
NO2
Br
Br
4
3
8
9
O
MeOOC
MeOOC
Br
iv
N
N
N
N
iii
N
N
N
N
NH2
NH2
R
O
O
Bn
Bn
iv
7
5, R = NO2
6, R = NH2
11
10
iii
O
Scheme 1. Reagents and conditions: (i) (1) SOCl2, cat. DMF, 80 °C,
16 h; (2) CH3OH, 0 °C, 30 min, 63%; (ii) NH3(g), CH3OH, 0 °C, 2 h,
89%; (iii) Raney–Ni, N2H4ÆH2O, CH3OH, reflux, 15 min, 83%; (iv) 3-
bromo-2-butanone, CH3CN, 100 °C, 3 h, 49%.
N
N
N
OH
12
imidazo[1,2-a]pyridine building block 7 (Scheme 1) was
synthesized with only minor modifications to the pub-
lished procedure.7b Starting from known 6-hydroxy-5-
nitronicotinic acid 3,13 chlorination and subsequent
careful treatment of the intermediate acid chloride with
methanol led to the carboxylic ester 4, which in turn
was reacted with gaseous ammonia to give the 2-
aminopyridine 5. On the other hand, when aqueous
ammonia was applied for the reaction, substantial
amounts of the corresponding carboxamide were ob-
tained as by-product. Subsequent reduction of the nitro
group of 5 led to the diaminopyridine 6 which, upon
treatment with 3-bromo-2-butanone, yielded the 8-
aminoimidazo[1,2-a]pyridine 7, required to access the
N-series of the target compounds 2 (Scheme 1).14
Scheme 2. Reagents and conditions: (i) 3-bromo-2-butanone, THF,
90 °C, 10 d, 65%; (ii) NaH, BnOH, DMF, rt, 20 h, 79%; (iii) Pd(OAc)2,
PPh3, THF, Et3N, 2 M Me2NH in THF, 10 bar CO, 120 °C, 16 h, 81%;
(iv) Pd/C (10%), EtOH, 1,4-cyclohexadiene, reflux, 3 h, 85%, Bn: benzyl.
substituted imidazo[1,2-a]pyridine ester 14 in good yield
and with high trans-selectivity (>95%). After saponifica-
tion of the ester 14 to the carboxylic acid 15, the carbox-
amides 16–19 were prepared by reaction of 15 with the
respective amine using TBTU17 as coupling reagent.
The low yield for the carboxamides 16 and 17 was
mainly due to losses during the workup procedure
(Scheme 3).
The analogous reaction of the 8-hydroxy-imidazo[1,2-
a]pyridine 12 with 1,2-epoxyindane (13) only proceeded
well in the presence of a base. The highest yield of the
The synthesis of the unknown 8-hydroxy-imidazo[1,2-
a]pyridine 12 (Scheme 2) started from commercially
available 2-amino-3,5-dibromopyridine (8), which was
reacted with 3-bromo-2-butanone to give the imi-
dazo[1,2-a]pyridine 9. Reaction of dibromo compound
9 with benzyl alkoxide provided regioselectively the 8-
O
R
O
N
O
i
benzyloxy-substituted
bromoimidazo[1,2-a]pyridine
7 +
N
10.15 The introduction of the carbonyl group in 6-posi-
tion of 10 was then effected by palladium-catalyzed
aminocarbonylation16: Heating a mixture of bromide
10, palladium acetate (15 mol %), triphenylphosphine
and dimethylamine (2 M solution in tetrahydrofuran)
under a pressure of 10 bar carbon monoxide furnished
directly the N,N-dimethylcarboxamide 11 in 81% yield.
Finally, cleavage of the benzyl ether by hydrogenation
of 11 provided the 8-hydroxy-imidazo[1,2-a]pyridine
12, which served as an entry to the O-series of the target
compounds 2 (Scheme 2).
NH
ii
13
14, R = CH3
15, R = H
OH
O
R'
N
N
iii
R''
15
N
NH
16: R' = R'' = H
17: R' = CH3, R'' = H
18: R' = R'' = CH3
OH
With the key intermediates 7 and 12 in hand, the synthe-
sis of the final compounds 2 had to be accomplished. In
the case of the N-series, simple heating of the 8-amino-
19: R' = 2-methoxyethyl, R'' = H
Scheme 3. Reagents and conditions: (i) dioxane, H2O, 100 °C, 60 h,
77%; (ii) dioxane, 2 N NaOH, reflux, 1 h, 73%; (iii) TBTU, CH2Cl2, rt,
16: NH3(g), 1.5 h, 10%, 17: 8 M MeNH2 in EtOH, 3 d, 20%, 18: 5.6 M
Me2NH in EtOH, 16 h, 73%, 19: 2-methoxyethylamine, 2 h, 56%.
imidazo[1,2-a]pyridine
7
with 1,2-epoxyindane 13
(Scheme 3) in a mixture of dioxane and water in the ab-
sence of a base provided the racemic 8-indanylamino-

5376
P. J. Zimmermann et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5374–5378
product 22 was obtained using triethylamine. As in the
case of the N-series, the trans-product was formed in a
selective manner (>95%). Additionally, we were inter-
ested in compounds carrying a substituent in 70-position
of the indane ring, since substituents such as 70-methyl
or 70-methoxy would further restrict the possible confor-
mations of the rotatable indanyl moiety. The required
7-methyl-1,2-epoxyindane (20) and 7-methoxy-1,2-epox-
yindane (21) were prepared from the corresponding
indenes by bromohydroxylation and subsequent epoxide
formation under basic conditions in analogy to the
known procedure for 1,2-epoxyindane (13).18 The reac-
tion of the amide 12 with the epoxides 20 and 21 pro-
ceeded sluggishly and provided the respective target
compounds 23 and 24 in low yields. Apparently, the
nucleophilic attack of the hydroxy group of 12 on the
epoxide ring is sterically hindered by the 7-substituent
adjacent to the benzylic position, thus leading to con-
comitant decomposition of the starting epoxides 20
and 21, respectively (Scheme 4).
All indanyl-substituted imidazo[1,2-a]pyridines 16–19 and
22–24, as well as the known P-CAB 1,19 were evaluated in a
competitive binding assay against H+/K+-ATPase from
hog gastric mucosa.6b Additionally, the lipophilicity and
pKa values of all the target compounds were determined.20
The results are summarized in Tables 1 and 2. The replace-
ment of the 2,6-dialkylbenzyl group of 1 by an indanyl
O
R
N
N
O
i
12 +
N
R
O
13: R = H
22: R = H
20: R = CH3
21: R = OCH3
23: R = CH3
24: R = OCH3
OH
Scheme 4. Reagents and conditions: (i) EtOH, H2O, Et3N, 22: 70 °C, 3 h, 51%, 23: 30 °C, 5 h, 20%, 24: 30 °C, 4 h, 19%.
Table 1. Inhibition of H+/K+-ATPase by compounds 1 and 16–19
R
N
N
NH
OH
H+/K+-ATPase
pKa
logPb,c
logD (pH 7.4)d
b
Compound
R
a
ꢀlogIC50
1
AR-HO47108
6.2
4.8
5.4
6.3
4.7
6.10 ( 0.01)
4.95 ( 0.08)
4.93
O
16
17
18
19
5.97 ( 0.02)
5.97 ( 0.02)
6.24 ( 0.02)
6.01 ( 0.04)
3.11 ( 0.05)
3.09
H2N
O
3.40 ( 0.04)
3.39
(H3C)HN
O
2.85 ( 0.05)
2.82
(H3C)2N
O
O
N
H
3.43 ( 0.05)
3.41
a For assay details, see Ref. 6b.
b See Ref. 20.
c 1-Octanol/water partition coefficient of the neutral species.
d 1-Octanol/water distribution coefficient at pH 7.4.

P. J. Zimmermann et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5374–5378
Table 2. Inhibition of H+/K+-ATPase by compounds 22–24
5377
O
N
N
N
O
R
H+/K+-ATPase
pKa
logPb,c
logD (pH 7.4)d
b
Compound
R
a
ꢀlogIC50
22
5.7
6.9
5.7
6.21 ( 0.02)
6.22 ( 0.02)
6.27 ( 0.01)
2.20 ( 0.06)
2.16
OH
CH3
23
24
2.59 ( 0.02)
2.56
OH
OH
OCH3
2.30 ( 0.05)
2.27
a For assay details, see Ref. 6b.
b See Ref. 20.
c 1-Octanol/water partition coefficient of the neutral species.
d 1-Octanol/water distribution coefficient at pH 7.4.
moiety (compound 16) led to an approximately 25-fold
reduction in activity (ꢀlogIC50 = 4.8). On the other hand,
a substantial increase in potency was observed when one of
the amide hydrogens of 16 was replaced by a methyl group
(17) and was even higher when both of the amide hydro-
gens were substituted by methyl (18). When the methyl
group of 17was replaced by 2-methoxyethyl (19), the activ-
ity again dropped considerably. The dimethylamide ana-
logue 22 of the O-series was less active than 18, but
introduction of a 70-methyl group (compound 23) in-
creased significantly the activity (ꢀlogIC50 = 6.9). How-
ever, the 70-methoxy derivative 24 was found to be
equipotent to 22. The replacement of the 2,6-dialkylbenzyl
group by indanyl did not change the basicity of the com-
pounds to a large extent (pKa values ranging from 5.97 to
6.24), but the lipophilicity was significantly reduced with
the more polar 3-hydroxy-indanyl moiety (16 vs 1). The in-
crease of the pKa value as well as the decrease of the logP
value of compound 18 compared to 16 and 17 is in agree-
ment with theoretical predictions using fragmental based
programs for pKa and logP calculations, such as ACD/
pKa DB, ACD/logP DB or clogP.21 As shown by compar-
ison of the dimethylamides 18 and 22, the lipophilicity was
even further decreased when the bridging nitrogen was re-
placed by oxygen.
pounds is comparable to that of the known P-CAB
AR-HO47108 (1).
Acknowledgments
We are grateful to Ms. S. Chrismann, Ms. G. Mu¨nch,
Ms. I. Hartig-Beecken and Ms. B. Bo¨ssenecker for tech-
nical assistance.
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5378
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