Synthesis and pharmacological evaluation of potential metabolites of the potassium-competitive acid blocker BYK 405879

Article abstract of DOI:10.1016/j.tetlet.2009.04.070

Four potential metabolites of the potassium-competitive acid blocker BYK 405879 (1) were synthesized which might be formed in vivo by enzymatic oxidation of the pyran moiety or the methyl groups attached to the (hetero) aromatic system. In all cases, the

Full text of DOI:10.1016/j.tetlet.2009.04.070

Tetrahedron Letters 50 (2009) 3917–3919
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and pharmacological evaluation of potential metabolites
of the potassium-competitive acid blocker BYK 405879
a
a
b
Andreas Marc Palmer a, , Gabriela Münch , Burkhard Grobbel , Wolfgang Kromer
*
a NYCOMED GmbH, Department of Medicinal Chemistry, Byk-Gulden-Str. 2, D-78467 Konstanz, Germany
b 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:
Four potential metabolites of the potassium-competitive acid blocker BYK 405879 (1) were synthesized
which might be formed in vivo by enzymatic oxidation of the pyran moiety or the methyl groups
attached to the (hetero) aromatic system. In all cases, the oxidation of the parent compound 1 was
accompanied by a significant loss of pharmacological activity and by a decrease in lipophilicity. The target
compounds 6, 14, 20, and 21 constitute valuable tool substances for the investigation of the metabolic
fate of BYK 405879 (1).
Received 3 March 2009
Revised 14 April 2009
Accepted 17 April 2009
Available online 23 April 2009
Keywords:
Phase I metabolism
Ó 2009 Elsevier Ltd. All rights reserved.
Potassium-competitive acid blocker
Pharmacological activity
Synthesis of potential metabolites
A drug has to face several stability challenges after oral admin-
istration until it finally reaches systemic circulation.1 During its
movement through the gut and the gut wall, it might undergo
intestinal decomposition and metabolism. In the liver, the mole-
cule might be transformed by monooxygenases (hepatic metabo-
lism). Once it has reached the blood stream, the substance might
be degraded by hydrolytic enzymes present in the plasma. Drug
metabolism, that is, the biotransformation of a drug, comprises
two phases. Whereas in phase I the molecular structure itself is
modified, in phase II polar groups are added to the molecular struc-
ture. The ultimate goal of drug metabolism is the production of
more polar products that possess higher aqueous solubility and
are more readily excreted from the body via bile and urine.
Recently, we wrote on the large-scale synthesis of the benz-
imidazole BYK 405879 (1) that constitutes a promising candidate
for further development as potassium-competitive acid blocker
(P-CAB).2 P-CABs might be an excellent option for the treatment
of a variety of gastrointestinal diseases, such as, for example, gas-
troesophageal reflux disease and gastric ulcer, and might be able to
overcome some of the limitations encountered during the therapy
with proton pump inhibitors (PPIs, current gold standard).3 In this
Letter, we describe the preparation and pharmacological activity of
several potential metabolites of BYK 405879 (1) that might be
formed during oxidative phase I metabolism. The test model (inhi-
bition of the pentagastrin-stimulated acid secretion in the Ghosh
Schild rat) was described previously.4
O
O
N
N
N
N
N
N
Ph
(i)
(ii)
HO
O
O
BYK 405879 (1)
2
O
O
OH
N
N
N
N
N
N
O
(iii)
Ph
Ph
HO
O
3
4
+
O
O
N
N
N
N
N
N
O
OH
O
(iv)
O
6
5
Scheme 1. Reagents and conditions: (i) t-BuOK, PhCHO, THF, rt, 17 h, 67%; (ii)
MsOH, HOAc, rt, 3 d, 88%; (iii) K2OsO4Á2H2O, NMO, citric acid, t-BuOH, H2O, rt, 17 h,
then Na2SO3, 32% 4, 39% 5; (iv) NaBH4, MeOH, rt, 1 h, 55%.
* Corresponding author. Tel.: +49 7531 844783; fax: +49 7531 8492087.
E-mail address: andreas.palmer@nycomed.com (A.M. Palmer).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.070

3918
A. M. Palmer et al. / Tetrahedron Letters 50 (2009) 3917–3919
For the preparation of the 2-hydroxymethyl metabolite 6, the
advantage of the acidic properties of the 2-methyl group of BYK
405879 was taken into consideration. (Scheme 1).
intermediate 8. The phenolic hydroxy group was protected by
transformation of 9 with benzyl bromide. The ortho-methylphenyl
moiety was installed by cross metathesis reaction of olefin 10 with
2-methylstyrene in the presence of second generation Grubbs cat-
alyst. A similar approach has already proven its value in the struc-
turally related imidazo[1,2-a]pyridine series.4 Bishydroxylation of
the double bond present in 11 was accomplished in quantitative
yield using potassium osmate(VI) dihydrate and N-methylmorpho-
line-N-oxide as reagents. Removal of the benzyl-protecting group
by catalytic hydrogenation afforded the triol 13 that was converted
under Mitsunobu conditions to the 7-hydroxy analog 14 of BYK
405879 (1). As in the case of the 2-hydroxymethyl derivative 6
the potential metabolite 14 inhibited the pentagastrin-stimulated
acid secretion in the Ghosh Schild rat in a less effective manner
Selective deprotonation of BYK 405879 (1) with potassium tert-
butylate and addition of the resulting anion to benzaldehyde affor-
ded the alcohol 2. The olefin 3 was secured by acid-catalyzed elim-
ination of water from intermediate 2. Oxidation of the double bond
with potassium osmate(VI) dihydrate/N-methyl-morpholine-N-
oxide yielded a mixture of diol 4 and aldehyde 5 which could be
separated by column chromatography. Finally, the 2-hydroxy-
methyl derivative 6 of BYK 405879 (1) was obtained by sodium-
borohydride-mediated reduction of aldehyde 5. Alcohol
(ED50 = 1.0 mol/kg) was found to be significantly less active than
the parent compound BYK 405879 (ED50 = 0.23 mol/kg).
6
l
l
The known building block 7 was used as starting material for the
synthesis of the potential 7-hydroxy metabolite 14 (Scheme 2).2
Functionalization of the heterocycle was accomplished by O-allyla-
tion of 7 and by subsequent Claisen rearrangement of the obtained
(ED50 = 2.0 lmol/kg) than the parent compound BYK 405879 (1).
Further metabolites of BYK 405879 (1) might be formed by oxi-
dation of the methyl group attached to the phenyl ring affording
the corresponding alcohol 20 or the aldehyde 21. Mannich base
O
O
O
O
N
N
(i)
N
N
(ii)
N
N
(iii)
N
N
(iv)
N
N
N
N
OH
O
OH
OBn
7
8
9
10
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
(v)
(vi)
(vii)
OBn
OBn
OH
OH
OH
O
HO
HO
HO
11
12
13
14
Scheme 2. Reagents and conditions: (i) allyl bromide, K2CO3, DMF, rt, 16 h, 78%; (ii) melting, 220 °C, 4 h, 81%; (iii) benzyl bromide, K2CO3, DMF, rt, 16 h, 100%; (iv) 2-
methylstyrene, 2nd generation Grubbs catalyst, CH2Cl2, 45 °C, 16 h, 60%; (v) K2OsO4Á2H2O, citric acid, NMO, t-BuOH, H2O, rt, 20 h, 100%; (vi) Pd/C, H2, EtOH, rt, 2 h, 90%; (vii)
PPh3, DIAD, THF, rt, 2 h, 38%.
O
O
N
N
N
N
N
N
O
N
N
N
N
(ii)
(i)
N
+
O
HO
OH
OH
OBn
OH
15
OBn
OBn
16
17
18
O
O
O
N
N
N
N
N
N
N
N
N
(iv)
(v)
(iii)
O
O
O
O
OBn
OH
H
19
20
21
O
O
O
O
O
(vi)
(vii)
OH
OBn
OBn
22
23
24
Scheme 3. Reagents and conditions. (i) toluene, 100 °C, 3 h, 51%; (ii) RuCl2[(S)-Xyl-P-Phos][(S)-DAIPEN], t-BuOK, 80 bar H2, 2-PrOH, t-BuOH, 70 °C, 17 h, 89%, 94.9% ee; (iii)
PPh3, DIAD, THF, rt, 2 h, 70%; (iv) H3PO4, 80 °C, 1 h, 36%; (v) SO3–pyridine, Et3N, DMSO, rt, 20 h; (vi) NaH, TBAI, BnBr, DMF, rt, 1–2 h, 57%; (vii) HCl, THF, 50 °C, 2 h, 94%.

A. M. Palmer et al. / Tetrahedron Letters 50 (2009) 3917–3919
3919
15 and enamine 16 were used as starting materials for the synthe-
sis of these target compounds (Scheme 3). The preparation of benz-
imidazole 15 was described previously.2 Enamine 16 was obtained
by titanium tetrachloride-mediated condensation of pyrrolidine
with 2-benzyloxymethylacetophenone 24. The latter compound
could not be prepared in a direct manner by benzyl protection of
2-hydroxymethylacetophenone and was synthesized from the
known acetal derivative 22 as depicted in Scheme 3.5 The prochiral
ketone 17 was isolated in 51% yield after heating a toluene solution
of 15 and 16 at 100 °C for 3 h. This substrate was reduced by asym-
metric hydrogenation in the presence of RuCl2[(S)-Xyl-P-Phos][(S)-
DAIPEN] and the corresponding chiral alcohol 18 was obtained in
excellent yield (89%) and optical purity (94.9% ee). The tetrahydro-
chromeno[7,8-d]imidazole scaffold was constructed by intramo-
lecular Mitsunobu reaction of diol 18. In order to avoid a possible
hydrogenolytic cleavage of the pyran ring present in 19, the ben-
zyl-protecting group was removed under acid-catalyzed conditions
affording the target compound 20. Finally, oxidation of the hydroxy
function of alcohol 20 to the corresponding aldehyde 21 was
accomplished under Parikh Doering conditions.6 The pharmacolog-
ical activity of alcohol 20 was evaluated in the Ghosh Schild rat
significant loss of pharmacological activity. As expected, all
hydroxy derivatives were found to be less lipophilic (6: log D = 2.5,
14 and 20: log D = 2.2) than the parent compound 1 (log D = 2.8).7
The target compounds 6, 14, 20, and 21 constitute valuable tool
substances for the investigation of the metabolic fate of BYK
405879 (1).
Acknowledgment
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. Kerns, E. H.; Di, L.. Chapter 11 in Drug-like Properties: Concepts Structure Design
and Methods—From ADME to Toxicity Optimization; Elsevier Academic Press:
Burlington, 2008.
2. Palmer, A. M.; Webel, M.; Scheufler, C.; Haag, D.; Müller, B. Org. Process Res. Dev.
2008, 12, 1170–1182.
3. (a) Schubert, M. L.; Peura, D. A. Gastroenterology 2008, 134, 1842–1860; (b)
Vesper, B. J.; Altman, K. W.; Elseth, K. M.; Haines, G. K., III; Pavlova, S. I.; Tao, L.;
Tarjan, G.; Radosevich, J. A. ChemMedChem 2008, 3, 552–559; (c) Scarpignato, C.;
Hunt, R. H. Curr. Opin. Pharmacol. 2008, 8, 677–684; (d) Shin, J. M.; Vagin, O.;
Munson, K.; Kidd, M.; Modlin, I. M.; Sachs, G. Cell. Mol. Life Sci. 2008, 65, 264–
281.
4. 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.
5. Kotali, A.; Lafazanis, I. S.; Christophidou, A. ARKIVOC 2003, 56–68.
6. Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505–5507.
7. The log D values were determined by HPLC.
(ED50 >3.0 lmol/kg) and it was found that the putative metabolite
20 was significantly less active than the parent compound 1.
In conclusion, four potential metabolites of the potassium-
competitive acid blocker BYK 405879 (1) were synthesized which
might be formed in vivo by enzymatic oxidation of the pyran moi-
ety or the methyl groups attached to the (hetero) aromatic system.
In all cases, the oxidation of the parent compound 1 resulted in a