Synthesis and pharmacological evaluation of 5-carboxamide-substituted tetrahydrochromeno[7,8-d]imidazoles

Article abstract of DOI:10.1016/j.tetlet.2009.04.071

A fast access to novel 5-carboxamide-substituted tetrahydrochromeno[7,8-d]imidazoles 4 was developed using the readily available preclinical candidate BYK 405879 (1) as starting material. The 5-amino function was installed by the Curtius rearrangement of

Full text of DOI:10.1016/j.tetlet.2009.04.071

Tetrahedron Letters 50 (2009) 3920–3922
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and pharmacological evaluation of 5-carboxamide-substituted
tetrahydrochromeno[7,8-d]imidazoles
a
b
c
Andreas Marc Palmer a, , Gabriela Münch , Christian Scheufler , Wolfgang Kromer
*
a NYCOMED GmbH, Department of Medicinal Chemistry, Byk-Gulden-Str. 2, D-78467 Konstanz, Germany
b NYCOMED GmbH, Department of Process Chemistry Research, Byk-Gulden-Str. 2, D-78467 Konstanz, Germany
c NYCOMED GmbH, Department of Pharmacology, Byk-Gulden-Str. 2, D-78467 Konstanz, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A fast access to novel 5-carboxamide-substituted tetrahydrochromeno[7,8-d]imidazoles 4 was developed
using the readily available preclinical candidate BYK 405879 (1) as starting material. The 5-amino func-
tion was installed by the Curtius rearrangement of carboxylic acid 2 or by the Hofmann rearrangement of
carboxamide 8 furnishing benzimidazole 3 as key intermediate. In the Ghosh Schild rat, some of the tar-
get compounds 10–14 showed noteworthy activity as potassium-competitive acid blockers.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 3 March 2009
Revised 14 April 2009
Accepted 17 April 2009
Available online 23 April 2009
Keywords:
Potassium-competitive acid blocker
Pharmacological activity
Curtius rearrangement
Hofmann rearrangement
Gastroesophageal reflux disease (GERD) is a condition that
develops when the reflux of stomach contents causes troublesome
symptoms and/or complications, such as heartburn, regurgitation,
or dysphagia.1 GERD is one of the most common gastrointestinal
disorders with an annual prevalence between 10% and 23%.2 The
introduction of irreversible proton pump inhibitors (PPIs) to the
market made evident that the inhibition of the gastric proton
pump (H+/K+-ATPase) constitutes a powerful approach for the
treatment of GERD.3 PPIs, such as pantoprazole, are able to provide
symptom relief, heal erosive esophagitis, and prevent further com-
plications. The goal of the present work was the synthesis and eval-
uation of potassium-competitive acid blockers (P-CABs) that
inhibit the H+/K+-ATPase in a reversible manner and might be able
to overcome some limitations that are encountered during the
treatment with PPIs.4
Recently, we reported the asymmetric synthesis of a series of
tetrahydrochromeno[7,8-d]imidazoles by asymmetric ketone
hydrogenation in the presence of the Noyori-type catalyst
RuCl2[(S)-Xyl-P-Phos][(S)-DAIPEN] and presented the large-scale
synthesis of the P-CAB BYK 405879 (1).5 In order to expand the
structure–activity relationship in the field of this structural class
we were interested in the synthesis of 5-amide-substituted deriv-
atives 4 in which the amide moiety is attached to the heterocyclic
core via the amino group.6
The hydrolysis of the carboxamide BYK 405879 (1) was a chal-
lenging task (Scheme 1). No transformation was observed applying
a variety of conditions that are generally suitable for the cleavage
of carboxamides. For instance, no reaction took place after pro-
longed treatment of BYK 405879 (1) with an excess of sodium
hydroxide (ethanol/water, 80 °C), potassium hydroxide (ethylene
glycol, 50–180 °C), potassium tert-butylate (tert-butanol, 2-propa-
nol or water, 60–100 °C), hydrochloric acid (pH 1, 80 °C), or triflu-
oroacetic acid (neat or aqueous solution, 100 °C). In 50% sulfuric
acid, BYK 405879 (1) was stable up to a temperature of 120 °C.
At 150 °C, unspecific decomposition reactions occurred. When a
solution of BYK 405879 (1) in hydrobromic acid/acetic acid was
stirred for 18 h at room temperature, cleavage of the pyran ring
took place. Heating of a solution of BYK 405879 (1) and potassium
hydroxide in ethylene glycol and water at 205 °C afforded a prod-
uct of high molecular weight (m/z = 728) along with untrans-
formed starting material. More encouraging results were
obtained when triethyloxonium tetrafluoroborate was employed
(1,2-dichloroethane, 90 °C): After a reaction time of 1 d, 30% con-
version was achieved and 18% of carboxylic acid 2 was detected
by HPLC/MS. Finally, it was found that the hydrolysis of BYK
405879 (1) could be accomplished in a convenient manner under
anhydrous conditions if a solution of 1 and sodium hydroxide in
ethylene glycol was heated to 190 °C and the water present in
the reaction mixture was removed by distillation. This afforded
the carboxylic acid 2 in 80% yield on 90 g scale.
The primary product of the Curtius rearrangement of acyl azides
* Corresponding author. Tel.: +49 7531 844783; fax: +49 7531 8492087.
E-mail address: andreas.palmer@nycomed.com (A.M. Palmer).
is an isocyanate which might be isolated or trapped by
a
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.071

A. M. Palmer et al. / Tetrahedron Letters 50 (2009) 3920–3922
3921
O
O
R''
N
H2N
R'
N
N
N
N
N
N
N
N
N
HO
O
(i)
O
O
O
O
BYK 405879(1)
2
3
4
Scheme 1. Reagents and conditions: (i) NaOH, ethylene glycol, removal of water, 190 °C, 17 h, 80%.
nucleophilic solvent. The reaction typically proceeds at 100 °C and
is considered as a concerted process that is accompanied by the
loss of nitrogen.7 The acyl azide starting material can be obtained
in a convenient manner by treatment of the carboxylic acid with
diphenylphosphoryl azide (DPPA).8 In order to convert the inter-
mediate isocyanate 6 directly into the corresponding tert-butyl-
carbamate 7, the Curtius rearrangement of the acyl azide 5 was
performed in tert-butanol (Scheme 2).
Table 1
The Curtius rearrangement of the carboxylic acid 2 to the tert-butyl carbamate 7
(DPPA, 4.0 equiv of Et3N, t-BuOH)
Entry
Equiv of DPPA
Temperature
Time (h)
Yield of 7
1
2
3
4
5
3.0
3.0
3.0
3.0
1.5
Reflux
Reflux
Reflux
50 °C
1
3
16
0.75
3
33%
32%
30%
26%a
b,c
Reflux
—
The acyl azide 5 was prepared in situ from carboxylic acid 2 and
DPPA. As can be seen from Table 1, the Curtius reaction of 2 was
studied in detail modifying the temperature, the reaction time,
and the stoichiometry of DPPA. Despite these efforts, the yield of
carbamate 7 never exceeded 33%. The best results were achieved
when the reaction was conducted in refluxing tert-butanol (cf. en-
tries 1–3 vs entry 4) using an excess of DPPA (3.0 equiv, cf. entries
1–3 vs entry 5). The reaction time had little influence on the iso-
lated yield of 7 (cf. entries 1–3). It was also attempted to conduct
the Curtius rearrangement in the absence of DPPA. However, at-
tempts to prepare the acyl azide 5 via activation of the carboxylic
acid 2 with thionyl chloride or TBTU and subsequent treatment of
the resulting intermediate with sodium azide were not successful.
Alternatively, the Hofmann rearrangement was investigated
a
The product 7 was obtained in 80% purity.
A different batch of starting material 2 was employed for this transformation.
Nonuniform and incomplete conversion.
b
c
the resulting N-bromoamide intermediate furnishes an isocyanate
that is cleaved under the prevailing aqueous conditions to the tar-
get amine that has one carbon atom less than the starting amide.9
Since the beginning of the 1990s the stable and commercially
available diacetoxyiodobenzene (DAIB) has been applied as re-
agent in the modified Hofmann rearrangement.10
The use of DAIB in methanolic potassium hydroxide solution at
5–10 °C generated methyl carbamates in good yields from the cor-
responding primary carboxamides. Indeed, when a methanolic
solution of carboxamide 8, DAIB (1.4 equiv), and potassium
hydroxide (2.5 equiv) was stirred for 2 h at 0 °C or at room temper-
ature, the carbamate 9 was obtained in 70–73% yield along with
traces of an undefined by-product. On the other hand, no reaction
occurred when tert-butanol was employed as solvent (35 °C, 4 h).
using the unsubstituted carboxamide
8 as starting material
(Scheme 2). The latter compound was obtained in excellent yield
by TBTU-mediated coupling of carboxylic acid 2 with ammonia.
Under classical Hofmann conditions, the respective carboxamide
is treated with sodium hypobromite. Concerted rearrangement of
O
O
H
OCN
O
N
N
N
N
N
N
N
N
N
HO
N3
O
(i)
O
O
O
O
2
5
6
7
(iii)
(ii)
O
H
OCN
O
N
H2N
N
N
N
N
N
H2N
(iv)
(v)
O
N
N
N
O
O
O
O
6
8
9
3
Scheme 2. Reagents and conditions: (i) DPPA, Et3N, t-BuOH, see Table 1; (ii) TFA, CH2Cl2, rt, 1 h, 59–85%; (iii) TBTU, EtN(i-Pr)2, DMF, 40 °C, 1 h, then NH3, MeOH, rt, 16 h, 84–
90%; (iv) PhI(OAc)2, KOH, MeOH, 0 °C or rt, 2 h, 70–73%; (v) NaOH, dioxane, 100 °C, 18 h, 42–59%.

3922
A. M. Palmer et al. / Tetrahedron Letters 50 (2009) 3920–3922
O
O
O
O
Br
N
H2N
N
N
N
N
N
N
N
Br
Cl
Cl
15
16
(i)
(ii)
O
O
O
10
3
11
ED50: 1.5 µmol/kg
ED50: 1.0 µmol/kg
(iii)
(iii)
(iii)
H
N
H
N
H
N
N
N
N
N
N
N
O
O
O
O
O
O
12
ED50: 0.6 µmol/kg
13
ED50: 1.4 µmol/kg
14
ED50: 0.4 µmol/kg
Scheme 3. Reagents and conditions: (i) 15, Et3N, THF, rt, 1 h, then t-BuOK, THF, 0 °C, 2 h, 39%; (ii) 16, Et3N, THF, rt, 1 h, then t-BuOK, THF, 0 °C, 2 h, 41% (containing traces of
12); (iii) RCOOH, TBTU, EtN(i-Pr)2, DMF, 40-45 °C, 0.75 h, then 3, rt, 2-22 h, R = c-Pr (12): 60%, R = c-Bu (13): 26%, R = Et (14): 48%.
The key intermediate 3 was obtained by cleavage of the carba-
mate 7 or 9 obtained by the Curtius rearrangement/Hofmann rear-
rangement, respectively (Scheme 2). Rapid conversion of the tert-
butyl carbamate 7 to the amine 3 occurred in the presence of triflu-
oroacetic acid (room temperature, 1 h, 85% yield). The methyl car-
The 5-amino function was installed by the Curtius rearrangement
of carboxylic acid 2 or by the Hofmann rearrangement of carbox-
amide 8 furnishing benzimidazole 3 as key intermediate. In the
Ghosh Schild rat, some of the target compounds 10–14 showed
noteworthy activity as potassium-competitive acid blockers with
bamate
9
was resistant against acid-catalyzed cleavage
ED50 values comparable to that of BYK 405879 (ED50 = 0.23 lmol/
(trifluoroacetic acid, dichloromethane, room temperature, 4 h, re-
flux, 2 h). However, smooth transformation to the amine 3 took
place, when a solution of methyl carbamate 9 in 1,4-dioxane and
aqueous sodium hydroxide (2 N) was heated overnight.
kg). A more detailed investigation of the structure-activity rela-
tionship within this new class of P-CABs appears to be worthwhile.
Acknowledgment
A two step sequence, comprising amide formation and nucleo-
philic substitution, was applied to complete the synthesis of target
compounds 10 and 11 containing a cyclic carboxamide residue
(Scheme 3). The piperidin-2-one derivative 10 was obtained in
39% yield by conversion of amine 3 with 5-bromopentanoyl chlo-
ride (15) and subsequent addition of potassium tert-butylate. In
the same manner, the pyrrolidin-2-one-substituted tetrahydro-
chromeno[7,8-d]imidazole 11 was prepared from amine 3 and 4-
bromobutanoyl chloride (16). In order to secure target compounds
12–14 containing an open-chain carboxamide residue, the respec-
tive carboxylic acid was activated by treatment with O-ben-
tetrafluoroborate
(TBTU) and was coupled with the 5-amino-substituted benzimid-
azole 3.
The pharmacological activity of the target compounds 10–14
was assessed in the Ghosh Schild rat, that is, the reduction of the
pentagastrin-stimulated acid secretion by the respective P-CAB
was determined as described previously (Scheme 3).11 The cyclo-
propylcarboxamide 12 and the propionamide 14 caused notewor-
We are grateful to Mr. W. Prinz for the pharmacological evalu-
ation of the target compounds in the Ghosh Schild rat.
References and notes
1. Vakil, N.; Van Zanten, S. V.; Kahrilas, P.; Dent, J.; Jones, R. Am. J. Gastroenterol.
2006, 101, 1900–1920.
2. Eslick, G. D.; Talley, N. J. J. Clin. Gastroenterol. 2008, 3. epub ahead of print.
3. Schubert, M. L.; Peura, D. A. Gastroenterology 2008, 134, 1842–1860.
4. (a) Vesper, B. J.; Altman, K. W.; Elseth, K. M.; Haines, G. K., III; Pavlova, S. I.; Tao,
L.; Tarjan, G.; Radosevich, J. A. Chem. Med. Chem. 2008, 3, 552–559; (b)
Scarpignato, C.; Hunt, R. H. Curr. Opin. Pharmacol. 2008, 8, 677–684; (c) Shin, J.
M.; Vagin, O.; Munson, K.; Kidd, M.; Modlin, I. M.; Sachs, G. Cell. Mol. Life Sci.
2008, 65, 264–281.
5. (a) Palmer, A. M.; Chiesa, V.; Holst, H. C.; Le Paih, J.; Zanotti-Gerosa, A.;
Nettekoven, U. Tetrahedron: Asymmetry 2008, 19, 2102–2110; (b) Palmer, A. M.;
Webel, M.; Scheufler, C.; Haag, D.; Müller, B. Org. Process Res. Dev. 2008, 12,
1170–1182.
zotriazol-1-yl-N,N,N0,N0-tetramethyluronium
6. Zimmermann, P. J.; Brehm, C.; Palmer, A.; Buhr, W.; Senn-Bilfinger, J.; Simon,
W.-A.; Herrmann, M.; Postius, S. International Patent Application WO 2008/
151927.
thy inhibition with ED50 values of 0.6
respectively. Ring expansion to the cyclobutylcarboxamide 13
was accompanied by a reduction of pharmacological activity
l
mol/kg and 0.4
l
mol/kg,
7. (a) Smith, P. A. S. Org. React 1946, 3, 337–449; (b) Linke, S.; Tisue, G. T.;
Lwowski, W. J. Am. Chem. Soc. 1967, 89, 6308–6310; (c) Banthorpe, D. V. In Patai
The Chemistry of the Azido Group; Wiley: NY, 1971; p 397.
8. Kim, D.; Weinreb, S. M. J. Org. Chem. 1978, 43, 125–131.
9. (a) Wallis, E. S.; Lane, J. F. Org. React. 1946, 3, 267–306; (b) Imamoto, T.; Kim, S.;
Tsuno, Y.; Yukawa, Y. Bull. Chem. Soc. Jpn. 1971, 44, 2776–2779.
10. (a) Beckwith, A. L. J.; Dyall, L. K. Aust. J. Chem. 1990, 43, 451–461; (b) Moriarty,
R. M.; Chany, C. J., II; Vaid, R. K.; Prakash, O.; Tuladhar, S. M. J. Org. Chem. 1993,
58, 2478–2482.
(ED50 = 1.4
lmol/kg). In the same manner, the cyclic carboxamides
10 (ED50 = 1.5
lmol/kg) and 11 (ED50 = 1.0 mol/kg) were found to
l
be significantly less active than their open chain analogs 12 and 14.
In conclusion, a fast access to novel 5-carboxamide-substituted
tetrahydrochromeno[7,8-d]imidazoles 4 was developed using the
readily available candidate BYK 405879 (1) as starting material.
11. Palmer, A. M.; Grobbel, B.; Jecke, C.; Brehm, C.; Zimmermann, P. J.; Buhr, W.;
Feth, M. P.; Simon, W.-A.; Kromer, W. J. Med. Chem. 2007, 50, 6240–6264.