Note: Descriptions are shown in the official language in which they were submitted.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
Isotopically Substituted Proton Pump Inhibitors
Subiect matter of the invention
The present invention relates to isotopically substituted proton pump
inhibitors and their (R)- and (S)-
enantiomers. These compounds can be used in the pharmaceutical industry for
preparing pharmaceu-
tical compositions.
Background of the invention
Owing to their H+/K+-ATPase-inhibitory action, pyridin-2-ylmethylsulphinyl-1 H-
benzimidazoles, such
as those known, for example, from EP-A-0005129, EP-A-0166287, EP-A-0174726, EP-
A-0254588 and
EP-A-0268956 are of considerable importance in the therapy of disorders
associated with an increased
secretion of gastric acid.
Examples of active compounds from this group which are commercially available
or in clinical develop-
ment are 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1 H-
benzimidazole (INN:
omeprazole), (S)-5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole
(INN: esomeprazole), 5-difluoromethoxy-2-[(3,4-dimethoxy-2-
pyridinyl)methylsulphinyl]-1 H-
benzimidazole (INN: pantoprazole), 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole (INN: lansoprazole), 2-{[4-(3-
methoxypropoxy)-3-
methylpyridin-2-yl]methylsulphinyl}-1 H-benzimidazole (INN: rabeprazole) and 5-
methoxy-2-((4-
methoxy-3,5-dimethyl-2-pyridylmethyl)sulphinyl)-1 H-imidazo[4,5-b]pyridine
(INN: tenatoprazole).
The above mentioned sulphinyl derivatives are, owing to their mechanism of
action, also referred to as
proton pump inhibitors or, abbreviated, as PPI.
Description of the related art
US Patent 6,818,200 discloses dihydropyridine compounds and antibiotics
wherein at least one hydro-
gen atom is replaced by a deuterium atom. The deuterated compounds are
obtained by reacting the H-
form with mixtures of deuterium oxide and a suitable catalyst in sealed
vessels at drastic reaction con-
ditions, i.e. at elevated temperatures (60-80 C) and for prolonged reaction
times (up to 190 hours). It
further discloses some influence on the pharmacological properties of these
compounds due to the
H/D exchange.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
2
Disclosure of the invention
It has now surprisingly been found that isotopically substituted compounds as
disclosed in detail below
influences significantly the inhibition of acid secretion.
The invention relates to compounds of the general formula 1
R2 R3
H
XZ N R4 (1)
_SN
R1 N O
in which
R1 is hydrogen or 1-4C-alkoxy
R2 is 1-4C-alkyl or 1-4C-alkoxy
R3 is 1-4C-alkyl, 1-4C-alkoxy or 2-8C-alkoxyalkoxy
R4 is hydrogen or 1-4C-alkyl
Z is C-H or N
and pharmaceutical acceptable salts, solvates, preferably hydrates, and
solvates, preferably hydrates
of the salts thereof, wherein at least one hydrogen atom of R1, R2, R3, R4 or
any combination of R1,
R2, R3 and R4 is replaced by a deuterium atom.
1-4C-Alkyl represents straight-chain or branched alkyl groups having 1 to 4
carbon atoms. Examples
which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl,
isopropyl, ethyl and, pref-
erably, the methyl group.
1-4C-Alkoxy represents a group, which in addition to the oxygen atom contains
one of the aforemen-
tioned 1-4C-alkyl groups or fluorinated 1-4C-alkyl groups. Examples for 1-4C-
alkyl groups which may
be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy,
isopropoxy, ethoxy and,
preferably, the methoxy group. Examples for fluorinated 1-4C-alkyl groups are
2,2,3,3,3-
pentafluoropropyl, 2,2,3,3-tetrafluoropropyl, 1-(trifluoromethyl)-2,2,2-
trifluoroethyl, 2,2,3,3,4,4,4-
heptafluorobutyl and, preferably, 2,2,2-trifluoroethyl and difluoromethyl.
2-8C-Alkoxyalkoxy represents a group, which in addition to the oxygen atom
contains an internal al-
kylene which contains 1-4C alkylene groups and a terminal alkyl group which
contains 1-4C alkyl
groups and being connected by an oxygen atom to the internal alkylene group.
Examples are meth-
oxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxypropoxy, ethoxyisopropoxy,
isopropoxymethoxy,
propoxymethoxy, methoxybutoxy, methoxyisobutoxy, propoxyethoxy,
isopropoxyethoxy, propoxypro-
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
3
poxy, isopropoxyisopropoxy, isopropoxypropoxy, propoxyisopropoxy,
ethoxybutoxy, ethoxyisobutoxy,
ethoxy-sec-butoxy, ethoxy-tert-butoxy and preferably methoxypropoxy.
According to the invention, within the meaning of salts all salts with
inorganic and organic bases are
included, in particular the salts with alkali metals, such as the lithium,
sodium and potassium salts, or
the salts with alkaline earth metals, such as the magnesium and calcium salts,
but also other pharma-
cologically compatible salts, such as, for example, the aluminium or the zinc
salts. Particularly pre-
ferred are the sodium and the magnesium salts.
Pharmacologically incompatible salts, which can initially be obtained, for
example, as process products
in the production of the compounds according to the invention on the
industrial scale, which are also
within the scope of the invention, are - for the production of pharmaceutical
compositions - converted
into the pharmacologically tolerable salts by processes known to the person
skilled in the art.
It is known to the person skilled in the art that the compounds according to
the invention and their
salts, if, for example, they are isolated in crystalline form, can contain
various amounts of solvents. The
invention therefore also comprises all solvates and in particular all hydrates
of the compounds of the
formula 1, and also all solvates and in particular all hydrates of the salts
of the compounds of the for-
mula 1. Within the meaning of solvates all pharmaceutically acceptable
solvents resulting in such sol-
vates are included.
Concerning the nomenclature of the compounds according to the invention the
terms "deutero" or
"deuterio" should indicate a deuterium atom ([2H]). Similarly, the pre-terms
"bis" or "di" and "tri" or "tris",
respectively should indicate the occurrence of two or three, for example
deuterio atoms in a specific
group, i.e. 1, 1 -dideuterio-2,2,2-trifluoroethoxy or trideuteriomethoxy .
Preferred within the scope of the invention are compounds of formula 1 wherein
at least one of the
hydrogen atoms of R3 is replaced by a deuterium atom and R3 is a 1-2C alkoxy
group or a 2-5C-
alkoxyalkoxy group.
Preferred are compounds of formula 1 wherein R2 is a 1-4C alkyl group and R3
is a 2-8C-alkoxyalkoxy
group, wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is
replaced by a deuterium
atom.
Preferred are compounds of formula 1 wherein R1 is a 1-4C alkoxy group, R2 and
R4 are a 1-4C alkyl
group and R3 is a 1-4C-alkoxy group, wherein at least one of the hydrogen
atoms of R1, R3, R4 or any
combination of R1, R3 and R4 is replaced by a deuterium atom.
Preferred are also compounds of formula 1 wherein R1 is hydrogen, methoxy or
difluoromethoxy, R2 is
methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, R4
is hydrogen or methyl
and wherein at least one of the hydrogen atoms of R3 is replaced by a
deuterium atom.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
4
Preferred are further compounds of formula 1 wherein R2 is methyl, R3 is
methoxypropoxy and Z is C-
H, wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is
replaced by a deuterium
atom.
Preferred are further compounds of formula 1 wherein R1 is methoxy, R2 and R4
are methyl and R3 is
methoxy, wherein at least one of the hydrogen atoms of R1, R3, R4 or any
combination of R1, R3 and
R4 is replaced by a deuterium atom. Possible combinations are R1 and R3, R1
and R4, R3 and R4,
R1 and R3 and R4.
Preferred are also compounds of formula 1 wherein R1 is methoxy, R2 is methyl,
R3 is methoxy, R4 is
methyl or wherein R1 is hydrogen, R2 is methyl, R3 is 2,2,2-trifluoroethoxy or
methoxypropoxy, R4 is
hydrogen or wherein R is difluoromethoxy, R2 is methoxy, R3 is methoxy, R4 is
hydrogen and wherein
at least one of the hydrogen atoms of R3 is replaced by a deuterium atom.
Preferred are further also compounds of formula 1 wherein R1 is methoxy, R2 is
methyl, R3 is meth-
oxy, R4 is methyl or wherein R1 is hydrogen, R2 is methyl, R3 is 2,2,2-
trifluoroethoxy or methoxypro-
poxy, R4 is hydrogen or wherein R is difluoromethoxy, R2 is methoxy, R3 is
methoxy, R4 is hydrogen
and wherein at least two of the hydrogen atoms of R3 are replaced by a
deuterium atom.
More preferred are compounds of formula 1 wherein R2 is a 1-4C alkyl group and
R3 is a 2-8C-
alkoxyalkoxy group, wherein all hydrogen atoms of R2, R3 or R2 and R3 are
replaced by deuterium
atoms.
More preferred are compounds of formula 1 wherein R1 is a 1-4C alkoxy group,
R2 and R4 are a 1-4C
alkyl group and R3 is a 1-4C-alkoxy group, wherein all hydrogen atoms of R1,
R3, R4 or any combina-
tion of R1, R3 and R4 are replaced by deuterium atoms. Possible combinations
are R1 and R3, R1
and R4, R3 and R4, R1 and R3 and R4.
More preferred are compounds of formula 1 wherein all hydrogen atoms of R3 are
replaced by deute-
rium atoms and wherein R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy.
More preferred are further compounds of formula 1 wherein R2 is methyl, R3 is
methoxypropoxy and Z
is C-H, wherein all hydrogen atoms of R2, R3 or R2 and R3 are replaced by
deuterium atoms.
More preferred are further compounds of formula 1 wherein R1 is methoxy, R2
and R4 are methyl and
R3 is methoxy, wherein all hydrogen atoms of R1, R3, R4 or any combination of
R1, R3 and R4 are
replaced by deuterium atoms. Possible combinations are R1 and R3, R1 and R4,
R3 and R4, R1 and
R3 and R4.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
More preferred are also compounds of formula 1 wherein R1 is hydrogen, methoxy
or difluoromethoxy,
R2 is methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or
methoxypropoxy, R4 is hydrogen or
methyl and wherein all hydrogen atoms of R3 are replaced by deuterium atoms.
More preferred are also compounds of formula 1 wherein R1 is methoxy, R2 is
methyl, R3 is methoxy,
R4 is methyl or wherein R1 is hydrogen, R2 is methyl, R3 is 2,2,2-
trifluoroethoxy or methoxypropoxy,
R4 is hydrogen or wherein R is difluoromethoxy, R2 is methoxy, R3 is methoxy,
R4 is hydrogen and
wherein all hydrogen atoms of R3 are replaced by deuterium atoms.
Most preferred are the compounds 5-methoxy-2-[(4-trideuteriomethoxy-3,5-
dimethyl-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-methoxy-2-[(4-
dideuteriomethoxy-3,5-dimethyl-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-trideuteriomethoxy-2-[(4-
methoxy-3,5-dimethyl-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-trideuteriomethoxy-2-[(4-
trideuteriomethoxy-3,5-
dimethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-trideuteriomethoxy-
2-[(4-dideuteriomethoxy-
3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-methoxy-2-[(3-
methyl-4-
trideuteriomethoxy-5-trideuteriomethyl-2-pyridinyl)methylsulphinyl]-1 H-
benzimidazole, 5-
trideuteriomethoxy-2-[(3-methyl-4-trideuteriomethoxy-5-trideuteriomethyl-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole, 2-[3-methyl-4-(1,1-dideuterio-
2,2,2-trifluoroethoxy)-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[(3-methoxy-
4-trideuteriomethoxy-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[(3-methoxy-
4-dideuteriomethoxy-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[(3-
trideuteriomethoxy-4-methoxy-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[(3-
dideuteriomethoxy-4-methoxy-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[(3,4-
bis(trideuteriomethoxy)-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[(3,4-
bis(dideuteriomethoxy)-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole, 2-{[4-(3-
trideuteriomethoxyhexadeuteriopropoxy)-3-
methylpyridin-2-yl]methylsulphinyl}-1 H-benzimidazole, 2-{[4-(3-
trideuteriomethoxyhexadeuteriopropoxy)-3-trideuteriomethylpyridin-2-
yl]methylsulphinyl}-1 H-
benzimidazole, 5-methoxy-2-((4-trideuteriomethoxy-3,5-dimethyl-2-
pyridylmethyl)sulphinyl)-1 H-
imidazo[4,5-b]pyridine, 5-trideuteriomethoxy-2-((4-trideuteriomethoxy-3,5-
dimethyl-2-
pyridylmethyl)sulphinyl)-1 H-imidazo[4,5-b]pyridine, 5-methoxy-2-((3-methyl-4-
trideuteriomethoxy-5-
trideuteriomethyl-2-pyridylmethyl)sulphinyl)-1 H-imidazo[4,5-b]pyridine or 5-
trideuteriomethoxy-2-((3-
methyl-4-trideuteriomethoxy-5-trideuteriomethyl-2-pyridylmethyl)sulphinyl)-1 H-
imidazo[4,5-b]pyridine.
According to the invention, the term "hydrogen atom replaced by a deuterium
atom" has to be under-
stood as defining a degree of deuteration of at least 80 % for the bulk
material, where all these corre-
spondingly mentioned hydrogen atoms are replaced by deuterium atoms. For
example, if the substitu-
ent R2 or R3 refers to a methoxy group having all three "hydrogen atoms
replaced by a deuterium
atoms" it is to be understood according to the above definition that at least
80% of all the R2 or R3
methoxy groups in the bulk material are -OCD3. The remaining part up to 100%
includes -OCHD2, -
OCH2D or-OCH3.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
6
Preferred is a degree of deuteration of at least 90% for the specific hydrogen
atom in the bulk material,
meaning that at least 90% of the replaced hydrogen atoms should be deuterium
atoms. More preferred
is a degree of deuteration of at least 92% for the specific hydrogen atom in
the bulk material. Even
more preferred is a degree of deuteration of at least 94% for the specific
hydrogen atom in the bulk
material and most preferred is a degree of deuteration of at least 96% for the
specific hydrogen atom in
the bulk material.
The compounds according to the invention are chiral compounds. The invention
thus relates to the
racemates as well as to the enantiomers and mixtures thereof in any desired
ratio. In view of the fact
that, from a medicinal point of view, it may be advantageous for certain
chiral compounds to be admin-
istered in the form of the one or the other enantiomer, a preferred subject
matter of the inventions are
the enantiomers of the compounds of formula 1, preferably the enantiomers
being substantially free of
the respective other enantiomer with opposite configuration.
Accordingly, particularly preferred are on one hand the compounds with (S)-
configuration of the gen-
eral formula 1a
R2 R3
H
N R4 (1a)
S:~. N
R1 Z N 0
in which R1, R2, R3, R4 and Z have the meanings given above.
Particularly preferred compounds with (S)-configuration within the scope of
the invention are the com-
pounds (S)-5-methoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-2-
pyridinyl)methylsulphinyl]-1 H-
benzimidazole, (S)-5-trideuteriomethoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-
2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole, (S)-5-methoxy-2-[(4-
dideuteriomethoxy-3,5-dimethyl-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole, (S)-5-trideuteriomethoxy-2-[(4-
dideuteriomethoxy-3,5-
dimethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole, (S)-5-
trideuteriomethoxy-2-[(4-methoxy-3,5-
dimethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole, (S)-5-methoxy-2-[(3-
methyl-4-
trideuteriomethoxy-5-trideuteriomethyl-2-pyridinyl)methylsulphinyl]-1 H-
benzimidazole, (S)-5-
trideuteriomethoxy-2-[(3-methyl-4-trideuteriomethoxy-5-trideuteriomethyl-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole or (S)-5-difluoromethoxy-2-[(3-
methoxy-4-
trideuteriomethoxy-2-pyridylmethyl)sulphinyl]-1 H-benzimidazole, (S)-5-
difluoromethoxy-2-[(3-methoxy-
4-dideuteriomethoxy-2-pyridylmethyl)sulphinyl]-1 H-benzimidazole and the
solvates, preferably hy-
drates of these compounds, the salts of these compounds and the solvates,
preferably hydrates of the
salts of these compounds.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
7
Particularly preferred are on the other hand the compounds with (R)-
configuration of the general for-
mula 1 b
R2 R3
H
/ N R4 (1 b)
\ ~ S ,,,,: N
R1 Z N O
in which R1, R2, R3, R4 and Z have the meanings given above.
A particularly preferred compound with (R)-configuration within the scope of
the invention is the com-
pound (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridylmethyl)sulphinyl]-1 H-
benzimidazole, (R)-5-difluoromethoxy-2-[(3-methoxy-4-dideuteromethoxy-2-
pyridylmethyl)sulphinyl]-
1 H-benzimidazole and the solvates, preferably hydrates of these compounds,
the salts of these com-
pounds and the solvates, preferably hydrates of the salts of these compounds.
The separation of the compounds of formula 1 into the enantiomers can be
accomplished according to
various processes, for example as described in international patent
application W092/08716 or by
column chromatography. Alternatively, the compounds of formulae 1a and 1 b can
be obtained by chiral
oxidation of the sulphides as described in international patent applications
W096/02535 or WO
2004/052881.
The salts of the compounds of formulae 1, 1 a and 1 b are prepared by
processes known per se by re-
acting the compounds of formulae 1, 1 a, and 1 b, which can be regarded as
weak acids, with suitable
bases, for example with alkali metal hydroxides or alkoxides, such as sodium
hydroxide or sodium
methoxide, or with alkaline earth metal alkoxides, such as magnesium
methoxide. As an example, the
magnesium salts of the compounds of formulae 1, 1 a and 1 b, which are -
besides the sodium salts -
the preferred salts, are prepared in a manner known per se by reacting
compounds of formulae 1, 1 a
and 1 b with a magnesium base, for example a magnesium alkoxide, or from a
readily soluble salt of a
compound of formulae 1, 1 a and 1 b (for example of a sodium salt) using a
magnesium salt in water or
in mixtures of water with polar organic solvents (for example alcohols,
preferably methanol, ethanol or
isopropanol, or ketones, preferably acetone).
According to the invention, "compounds with (S)-configuration" is understood
to include "compounds
with (S)-configuration being substantially free of compounds with (R)-
configuration".
"Substantially free" in the context of the invention means that the compounds
with (S)-configuration
and/or their salts, solvates or solvates of salts contain less than 10 % by
weight of compounds with
(R)-configuration and/or their salts, solvates or solvates of salts.
Preferably, "substantially free" means
that compounds with (S)-configuration and/or their salts, solvates or solvates
of salts contain less than
% by weight of compounds with (R)-configuration and/or their salts, solvates
or solvates of salts.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
8
More preferably, "substantially free" means that compounds with (S)-
configuration and/or their salts,
solvates or solvates of salts contain less than 2 % by weight of compounds
with (R)-configuration
and/or their salts, solvates or solvates of salts. In the most preferred
embodiment, "substantially free"
means that compounds with (S)-configuration and/or their salts, solvates or
solvates of salts contain
less than 1% by weight of compounds with (R)-configuration and/or their salts,
solvates or solvates of
salts.
According to the invention, "compounds with (R)-configuration" is understood
to include "compounds
with (R)-configuration being substantially free of compounds with (S)-
configuration".
"Substantially free" in the context of the invention means that the compounds
with (R)-configuration
and/or their salts, solvates or solvates of salts contain less than 10 % by
weight of compounds with
(S)-configuration and/or their salts, solvates or solvates of salts.
Preferably, "substantially free" means
that compounds with (R)-configuration and/or their salts, solvates or solvates
of salts contain less than
% by weight of compounds with (S)-configuration and/or their salts, solvates
or solvates of salts.
More preferably, "substantially free" means that compounds with (R)-
configuration and/or their salts,
solvates or solvates of salts contain less than 2 % by weight of compounds
with (S)-configuration
and/or their salts, solvates or solvates of salts. In the most preferred
embodiment, "substantially free"
means that compounds with (R)-configuration and/or their salts, solvates or
solvates of salts contain
less than 1% by weight of compounds with (S)-configuration and/or their salts,
solvates or solvates of
salts.
Additional subject matter of the invention are compounds of formula 2
R2 R3
H
/ N / R4 (2)
~ S N
R1 Z N
in which R1, R2, R3, R4 and Z have the meanings as given above and wherein at
least one of the
hydrogen atoms of R1, R2, R3, R4 or any combination of R1, R2, R3 and R4 is
replaced by a deute-
rium atom, and their salts, such as the hydrochloride, the sulfate, the
phosphate or other salts with
acids, and their solvates. These compounds can be used for the manufacture of
compounds of general
formula 1, 1 a or 1 b. The compounds of formula 2 are suitable especially as
starting material for an
oxidation reaction resulting in compounds according formulae 1, 1 a or 1 b.
Another aspect of the invention are compounds of formula 3
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
9
R2 R3
R4
X N
(3)
in which X is a halogen or an activated derivative of an alcohol and R2, R3
and R4 have the meanings
as given above and wherein at least one of the hydrogen atoms of R2, R3 and/or
R4 is replaced by a
deuterium atom.
Preferred are compounds of formula 3 wherein R2 is methyl or methoxy, R3 is
methoxy, 2,2,2-
trifluoroethoxy or methoxypropoxy, R4 is hydrogen or methyl and wherein at
least one of the hydrogen
atoms of R3 is replaced by deuterium atoms.
More preferred are compounds of formula 3 wherein R2 is methyl, R3 is methoxy,
R4 is methyl or R2
is methoxy, R3 is methoxy, R4 is hydrogen or R2 is methyl, R3 is 2,2,2-
trifluoroethoxy or methoxypro-
poxy, R4 is hydrogen and wherein at least one of the hydrogen atoms of R3 is
replaced by deuterium
atoms.
Also more preferred are compounds of formula 3 wherein R2 is methyl, R3 is
methoxy, R4 is methyl or
R2 is methoxy, R3 is methoxy, R4 is hydrogen or R2 is methyl, R3 is 2,2,2-
trifluoroethoxy or meth-
oxypropoxy, R4 is hydrogen and wherein at least two or all of the hydrogen
atoms of R3 are replaced
by deuterium atoms.
For the purpose of the invention, halogen is iodine, bromine, chlorine and
fluorine. Preferably X is chlo-
rine. An activated derivative of an alcohol is an alkylsulfonate group, for
example mesylate or an aryl-
sulfonate group, for example tosylate or besylate, or a
perfluoroalkanesulfonate group, for example
trifl uormethanesu Ifonate.
Related to a compound of formula 3 and thus an aspect of the invention is a
compound of formula 3a
R2 R5
R4
X N
(3a)
in which X, R2 and R4 have the meanings as given above, R5 being chloro or
nitro and wherein at
least one of the hydrogen atoms of R2 and/or R4 is replaced by a deuterium
atom.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
Preferred are compounds of formula 3a wherein R2 is methyl or methoxy, R4 is
hydrogen or methyl
and wherein at least one of the hydrogen atoms of R2 and/or R4 is replaced by
deuterium atoms.
More preferred are compounds of formula 3a wherein R2 and R4 are methyl and
wherein at least one
of the hydrogen atoms of R2 and/or R4 is replaced by deuterium atoms.
The compounds of formula 3 can be used for the manufacture of compounds of
formula 1, 1 a or 1 b.
Preferably the nitrogen atom of compound of formula 3 is first quaternised and
then reacted with com-
pounds of formula 4
H
~ N (4)
~ ~SH
R1 Z N
in which R1 and Z have the meaning as given above, thus providing compounds of
formula 2 as de-
scribed above.
The compounds of formula 3a can be used for the manufacture of compounds of
formula 2a.
R2 R5
H
N R4 (2a)
S N
R1 Z N
in which R1, R2, R5, R4 and Z have the meanings as given above and wherein at
least one of the
hydrogen atoms of R1, R2, R4 or any combination of R1, R2 and R4 is replaced
by a deuterium atom.
Preferably the nitrogen atom of compound of formula 3a is first quaternised
and then reacted with com-
pounds of formula 4
H
~ >_SH
X N (4)
R1 Z N
in which R1 and Z have the meaning as given above, thus providing compounds of
formula 2a as de-
scribed above.
Compounds of formula 2a can be used for the manufacturing of compounds of
formula 2 by substitut-
ing the residue R5 with a residue R3, both having the meanings as described
above. Under the proviso
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
11
that none of the hydrogens of R1, R2 or R4 are replaced by a deuterium atom,
at least one of the hy-
drogen atoms of R3 is replaced by a deuterium atom.
Another aspect of the invention are compounds of formula 4
H
I ~SH
XZ CN '4)
R1 N
wherein R1 is 1-4C alkoxy, Z is C-H or N and wherein at least one of the
hydrogen atoms of R1 is re-
placed by a deuterium atom. Preferably R1 is methoxy. These compounds may be
used for the manu-
facture of compounds of formula 1 or 2.
More preferred are compounds wherein R1 is methoxy and wherein all hydrogen
atoms of R1 are re-
placed by deuterium atoms.
The deuterium homologes of the proton pump inhibitors and for example of R/S
pantoprazole and S-
pantoprazole are prepared by oxidation of the corresponding thio-compounds
according to methods
known from literature, e.g. Kohl et al. J. Med. Chem. 1992, 35, 1049 ff. or WO
2004/052881 or by ex-
change of halogen for trideuteriomethoxy from the corresponding sulfoxides
with a halogen (e.g.
chloro, bromo or nitro) substituent at the position of the final
trideuteriomethoxy group, in particular in
4-position of the pyridin group. Similar as described before an exchange of
the halogen by dideute-
riomethoxy or monodeuteriomethoxy will lead to the correspondingly deuterated
compounds.
In analogy the thiocompounds are prepared either by exchange of halogen by
mono-, di- or trideute-
riomethoxy at the position of the final mono-, di- or trideuteriomethoxy-
substituent or by coupling of 5-
difluoromethoxy-2-mercaptobenzimidazole with the accordingly substituted 2-
chloromethyl-3-methoxy-
4-trideuteriomethoxy-pyridinumchloride.
The compound of formula 1 can be prepared according to the following reaction
scheme:
R3 R3
R2 :&" R4 R2 I~ R4
X N+
3 5 H CI
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
12
R3
R2 R4
X I +
R2 R3
N
~ N H CI H
R4
N
I /SH ::r
R1 Z N 1. KOH / EtOH //S N
(80-C) R1 N
4
2
R2 R3 R2 R3
/ N R4 Oxidation N R4
\ I /S N / ~ \ I /S~ N
R1 Z N R1 Z N O
2
Salts of the sulfoxides with anorganic bases are prepared according to methods
known from literature
by reaction of the sulfoxides with the corresponding hydroxides or alkoxides
in organic solvents or
mixtures of organic solvents with water.
Alternatively salts are prepared by reaction of sulfoxides with alkali
hydroxides to give the correspond-
ing alkali salt (Na, K, Li) and further reaction with e.g. magnesium, calcium,
aluminum, zinc salts.
The following examples serve to illustrate the invention in greater detail
without restricting it to the de-
scribed examples. The other above mentioned compounds can be obtain by using
the described meth-
ods.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
13
Examples
As trideuteriomethoxylation agent, methanol-d4 with >99.8 atom% D was used.
Isomeric purity of the
trideuteriomethoxy substituent(s) in all resulting products was >98.0% as
determined by NMR and MS.
As further deuteration agents, methanol-d2 with >98.0 atom% D, and methanol-d1
with >98.0 atom%
D were used. Isomeric purity of the dideuteriomethoxy and monodeuteriomethoxy
substituents in the
resulting products was >96.0% as determined by NMR and MS.
Example I
5-Difluoromethoxy (R/S) 2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole
A solution of sodium hypochlorite (10 % strength) (3.3 mMol) is added over one
to two hours to a slurry
of 5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)
methylthio]-1 H-benzimidazole
(1.0 g, 2.7 mMol) in water (20 mL), 2-propanol (10 mL) and sodium hydroxide
(0.5 mL 40 % strength
solution, 7.1 mMol) at 30 - 35 C with stirring. After 30 - 60 minutes at the
stated temperature sodium
thiosulfate (0.3 g dissolved in 5 mL of water) is added and stirring is
continued for a further 15 - 30
minutes.
The reaction mixture is concentrated in vacuo (30 - 40 C) to about one third
of the original volume
and water (about 70 mL) is added.
After extraction of the water phase with dichloromethane (2 x 10 mL each)
again dichloromethane (50
mL) is added and the pH is adjusted to 7- 8 by addition of aqueous potassium
dihydrogenphosphate
while stirring. Phase separation, one further extraction of the water phase
with dichloromethane (20
mL), washing of the combined organic phases with water (20 mL) drying with
magnesium sulfate and
filtration of the drying agent gives a solution of the crude title compound.
Addition of petroleum ether (50/70; 150 mL) and concentration in a rotary
evaporator in vacuo at 30 -
40 C to about 30 mL volume followed by filtration of the precipitated solid,
rinse with petroleum ether
50/70 (20 mL) and drying in vacuo (35 C, 5 hours) yields the title compound 5-
difluoromethoxy (R/S)
2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl]-1 H-
benzimidazole as an off white solid
of m. p. 135 - 136 C (decomp.); yield 1.0 g(95 % of theoretical).
'H-NMR (400 MHz, DMSO d-6): d = 3,78 (s, 3 H, OMe), 4,68 (d, 1 H, J(CHa,CHb) =
13 Hz, S-CH2-Py),
4,73 (d, 1 H, J(CHb,CHa) = 13 Hz, S-CH2-Py), 7,10 (d, 1 H, J(H5',H6') = 5 Hz,
H5') 7,18 (bd, 1 H, H6),
7,24 (t, 1 H, J(H,F) = 74 Hz, OCHF2), 7,4 (bs, 1 H, H4), 7,70 (bs, 1 H, H7),
8,15 (d, 1 H, J(H6',H5') = 5
Hz, H6'), 13,7 (s, 1 H, NH).
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
14
Example 2
S(-)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole
At room temperature, 2.0 g of 5-difluoromethoxy-2-[(3-methoxy-4-
trideuteriomethoxy-2-
pyridinyl)methylthio]-1 H-benzimidazole are suspended in 20 mL of methyl
isobutyl ketone together with
(+)-L-tartaric acid bis-(N-pyrrolidinamide) (2.3 g) and zirconium (IV) n-
propoxide (1.0 g, 70 % in
propanol). The mixture is heated at 40 C for one hour, resulting in the
formation of a solution which is
almost clear. After cooling to room temperature, N-ethyldiisopropylamine (0.07
mL) and cumene hy-
droperoxide (1.05 mL) are added. The mixture is stirred at room temperature
until the oxidation has
ended (10 - 24 hours, monitored by TLC). The clear solution is diluted with 10
mL of methyl isobutyl
ketone and quenched with 0.08 g of sodium thiosulphate in 14 mL of saturated
sodium bicarbonate
solution and stirred for a further 2 hours. After phase separation the mixture
is washed twice with 5 mL
of saturated sodium bicarbonate solution. 15 mL of water are added to the
methyl isobutyl ketone
phase, and the pH is adjusted to pH = 13 using a 40 % by weight strenghth
solution of sodium hydrox-
ide. After phase separation, the methyl isobutyl ketone phase is extracted
with another 5 mL of water
at pH 13. The aqueous phases are combined and, at 40 C, subjected to
incipient distillation under
reduced pressure. Hyflo Super Cell as filtration aid (0.05 g) is added and
after stirring for one hour at
20 - 25 C filtered off. At 40 - 45 C, the crude title compound is
precipitated by addition of 10 %
strength acetic acid to the filtrate to pH = 9Ø The mixture is stirred for
another 12 hours during which
the pH is monitored. The beige crystals are filtered off and washed with 10 mL
of water. The title com-
pound is obtained in a yield of about 1.6 g (75 % of theory) and an optical
purity of > 98 %.
To increase the purity, (-) trideuteriopantoprazole is dissolved in
water/aqueous sodium hydroxide so-
lution at pH = 13 and re-precipitated with acetic acid (10 %) at pH = 9Ø
Recrystallisation from dichloromethane/tert-butylmethylether gives the title
compound S(-)-5-
difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulphinyl]-1 H-benzimidazole as
an offwhite solid of m. p. 146-148 C (decomp.); yield 1.6 g.
Example 3
Synthesis of starting material 2-chloromethyl-3-methoxy-4-trideuteriomethoxy
pyridiniumchloride
Preparation of 3-methoxy-2-methyl-4-trideuteriomethoxypyridine N-oxide
4-chloro-3methoxy-2-methylpyridine N-oxide (10 g) and sodium
trideuteriomethanolate (6.2 g) in deu-
teromethanol D4 (20 mL) were heated at reflux. After 15 hours the solvent was
evaporated in vacuo,
the residue was extracted with hot toluene (50 mL) and the insolubles were
filtered off. Addition of
diisopropylether to the filtrate precipitated a solid, which after drying in
vacuo yielded 8.1 g of 3-
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
methoxy-2-methyl-4-trideuteriomethoxypyridine N-oxide as a light brown powder.
It was subsequently
used in the following step.
Preparation of 2-hydroxymethyl-3-methoxy-4-trideuteriomethoxypyridine
The product (8.1 g) from the previous step was dissolved in acetic anhydride
(50 mL) and was heated
at 90 C for 2 hours. After evaporation in vacuo, the dark oily residue was
agitated with 2N NaOH (20
mL) for 2 hours at 80 C. After cooling the product was extracted into
dichloromethane, dried (K2C03),
and concentrated in vacuo to low volume. Addition of petroleum ether (50/70)
afforded, after filtration
and drying in vacuo 2-hydroxy-3-methoxy-4-trideuteriomethoxypyridine as light
brown solid (5.5 g)
which was used in the following step.
Preparation of 2-chloromethyl-3-methoxy-4-trideuteriomethoxy pyridinium
chloride
The product form the previous step (5.5 g) was dissolved in dry
dichloromethane (40 mL) and thionyl-
chloride (3 mL) was added dropwise at 5- 10 C while stirring. The mixture was
allowed to warm up to
C and after 3 hours evaporated to dryness in vacuo.
Addition of toluene (20 mL) yielded 6.6 g of the title compound 2-chloromethyl-
3-methoxy-4-
trideuteriomethoxypyridinium chloride as light brown solid.
Material synthesized in this manner contained some difficult-to-remove
impurities, which showed a
propensity to get carried through the next steps leading to compounds of
general formula (2) and, ulti-
mately, general formula (1). For the preparation of compounds of general
formula (1) with exceptionally
high purity, it is therefore frequently preferable to resort to the
deuterioalkoxylation method featured in
Examples 9 and 35.
Example 4
4-Chloro-2-chloromethyl-3-methoxypyridinium chloride
At 85-95 C, a solution of 4-chloro-3-methoxy-2-methylpyridine-N-oxide (19.2
kg, 111 mol) in toluene
(148 L), was added over 5-7 h to acetic anhydride (71 L). Under vacuum at
about 60 C, the reaction
mixture was concentrated until about 170 L had been distilled off. Toluene
(160 L) was added and,
again, solvents were distilled off (160 L). This last operation was repeated
once more. Then, toluene
(14 L) and 40% aqueous NaOH (14.6 L) were added at 35-45 C and the reaction
mixture was kept at
this temperature for 2-3 h. If at this point pH was below 13, more NaOH was
added and heating con-
tinued for 2 more h. The resulting biphasic reaction mixture was diluted with
toluene (26 L) and satu-
rated aqueous sodium bicarbonate (26 L), the phases were separated and the
aqueous layer was
extracted thrice more with toluene (26 L and 2 x 13 L). Finally, the combined
organic phase was
washed with saturated aqueous sodium bicarbonate (13 L) and concentrated under
vacuum at 50-65
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
16
C until about 115 L had been distilled off. After dilution with toluene (100
L), another 100 L of solvents
were distilled off.
The resulting solution of 4-chloro-2-hydroxymethyl-3-methoxypyridine (-30%
strength) was diluted with
CH2CI2 (48 L). DMF (65.5 g, 0.896 mol) was added in one portion and, then,
thionyl chloride (11.1 kg,
93.2 mol) over 3-5 h at 15-30 C. After stirring for additional 1.5 h, about
45 L of solvents were distilled
off. Toluene (20 L) was added and, again, 20 L of solvents were removed by
distillation. Then, ethanol
(1.5 L) was added to the resulting thick slurry. The solids were filtered off
at 10-15 C, washed with
toluene (17 L) and dried in vacuo at 30 C to give 4-chloro-2-chloromethyl-3-
methoxypyridinium chlo-
ride as an off-white solid (m. p. 132 C); yield 15.0 kg (59%).
'H-NMR (200 MHz, CDCI3): S= 4.19 (s, 3H), 5.14 (s, 2H), 7.92 (d, 6.0 Hz, 1 H),
8.59 (d, 6.0 Hz, 1 H),
11.64 (br s, 1 H); LC-MS: MH' = 192/194/196.
Example 5
4-Chloro-2-chloromethyl-3-trideuteriomethoxypyridinium chloride
Starting material, 4-chloro-2-methyl-3-trideuteriomethoxypyridine-N-oxide was
prepared according to
method D for the non-deuterated analogue in J. Med. Chem. 1992, 35, 1049-1057:
Starting from 3-hydroxy-2-methyl-4-pyrone, conversion with trideuterio-
iodomethane in the presence of
potassium carbonate in DMF yielded 2-methyl-3-trideuteriomethoxy-4-pyrone
(yield: 83-96%), which
upon heating with ammonia at 150 C in ethanol gave, after crystallization
from acetone/isopropanol
4:1; 4-hydroxy-2-methyl-trideuteriomethoxypyridine (yield: 52-60%). Treatment
of this material with
phosphorus oxychloride led to formation of 4-chloro-2-methyl-
trideuteriomethoxypyridine (yield: 64-
81 %). Subsequent oxidation with hydrogen peroxide in acetic acid gave 4-
chloro-2-methyl-3-
trideuteriomethoxypyridine-N-oxide as a slightly yellow solid (yield: 87-89%).
The final transformations via 4-chloro-2-hydroxymethyl-3-
trideuteriomethoxypyridine were carried out
as described under Example 4 to give 4-chloro-2-chloromethyl-3-
trideuteriomethoxypyridinium chloride
as a colorless crystalline solid (m. p. 129-130 C); yield 19.6 g (42%).
Example 6
2-Chloromethyl-3,4-bis(trideuteriomethoxy)pyridinium chloride
According to the procedure described under Example 3, 4-chloro-2-methyl-3-
trideuteriomethoxypyridine-N-oxide (25.3 g, 144 mmol; for preparation see
Example 5) was converted
into 2-methyl-3,4-bis(trideuteriomethoxy)pyridine-N-oxide (yield: 23.5 g,
96%), which, in turn, gave 2-
hydroxymethyl-3,4-bis(trideuteriomethoxy)pyridine (yield: 13.0 g, 56%) and,
ultimately, 2-chloromethyl-
3,4-bis(trideuteriomethoxy)pyridinium chloride (yield: 15.4 g, 89%) as an off-
white crystalline solid.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
17
Example 7
5-Difl uoromethoxy-2-[(4-chloro-3-methoxy-2-pyridinyl)methylthio]-1 H-
benzimidazole
At 55-65 C, a solution of 4-chloro-2-chloromethyl-3-methoxypyridinium
chloride (10.0 kg, 43.8 mol) in
water (20 L) was added over 2-3 h to a mixture of 5-trideuteriomethoxy-1 H-
benzimidazole-2-thiol (8.84
kg, 40.9 mol), toluene (43 L), water (21 L) and 40% aqueous NaOH (10.3 kg, 103
mol). Stirring at 60
C was continued for 2-3 h before the reaction mixture was cooled to 10-15 C.
The precipitate was
centrifuged off, washed with toluene (16 L) and re-pulped in water (122 L).
Centrifugation followed by
an aqueous rinse (32 L) and drying at 35 C in vacuo gave 5-difluoromethoxy-2-
[(4-chloro-3-methoxy-
2-pyridinyl)methylthio]-1 H-benzimidazole mono hydrate (KF = 4.6%) as an off-
white solid (m. p. 95-99
C); yield 14.2 kg (92%).
1H-NMR (200 MHz, DMSO-d6): S= 3.55 (br s, NH + H20), 3.92 (s, 3H), 4.79 (s,
2H), 6.97 (dd, 8.6 Hz,
2.3 Hz, 1 H), 7.16 (t, 74.8 Hz, 1 H), 7.28 (d, 2.2 Hz, 1 H), 7.47 (d, 8.7 Hz,
1 H), 7.55 (d, 5.3 Hz, 1 H), 8.25
(d, 5.2 Hz, 1 H); LC-MS: MH' = 372/374.
Example 8
5-Difluoromethoxy-2-[(4-chloro-3-trideuteriomethoxy-2-pyridinyl)methylthio]-1
H-benzimidazole
Starting from 4-chloro-2-chloromethyl-3-trideuteriomethoxypyridinium chloride
(5.00 g, 21.6 mmol) and
following the procedure described under Example 7, 5-difluoromethoxy-2-[(4-
chloro-3-
trideuteriomethoxy-2-pyridinyl)methylthio]-1 H-benzimidazole mono hydrate (KF
= 4.7%) was obtained
as an off-white solid (m. p. 94-99 C); yield 7.24 g (85%).
1H-NMR (200 MHz, DMSO-d6): S= 4.79 (s, 2H), 6.98 (dd, 8.7 Hz, 2.3 Hz, 1 H),
7.16 (t, 74.8 Hz, 1 H),
7.28 (d, 2.0 Hz, 1 H), 7.47 (d, 8.6 Hz, 1 H), 7.55 (d, 5.2 Hz, 1 H), 8.25 (d,
5.2 Hz, 1 H), 12.75 (br s, 1 H);
LC-MS: MH' = 375/377.
Example 9
5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1
H-benzimidazole
At 15-30 C, methanol-d4 (2.26 kg, 62.7 mol) was added over 30-60 min to a
mixture of sodium tert-
butoxide (6.00 kg, 62.4 mol) in DMAc (27 L). After heating to 57-65 C, a
solution of 5-difluoromethoxy-
2-[(4-chloro-3-methoxy-2-pyridinyl)methylthio]-1l-l-benzimidazole mono hydrate
(6.08 kg, 15.6 mol) in
DMAc (10 L) was added over 30-60 min. Stirring at 57-65 C was continued for
about 10 h. The reac-
tion mixture was cooled to 20-30 C and diluted with water (21 L) before the
pH was adjusted to 7-8
with 20% aqueous HCI (-7.5 L). Precipitation of product was achieved by
addition of water (75 h) over
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
18
about 4 h. The resulting slurry was heated to 35-45 C for 1.5 h before being
chilled to 10-15 C. 5-
difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H-
benzimidazole was
obtained as a water-wet brownish solid by centrifugation including an aqueous
rinse (58 L), re-pulping
in water (78 L) and, again; centrifugation including another aqueous rinse (58
L); yield 10.4 kg, KF =
49.7% (91%).
Drying of a sample of water-wet product (16.2 g, KF = 49.7 %) at 25 C in
vacuo gave an amorphous
solid, which upon crystallization from toluene (30 mL) yielded water-free 5-
difluoromethoxy-2-[(3-
methoxy-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H-benzimidazole as an
off-white solid (5.80 g,
71 % recovery, m. p. = 115-116 C).
'H-NMR (200 MHz, DMSO-d6): S= 3.82 (s, 3H), 4.68 (s, 2H), 6.97 (dd, 8.6 Hz,
2.1 Hz, 1 H), 7.08 (d,
5.6 Hz, 1 H), 7.16 (t, 74.8 Hz, 1 H), 7.28 (br s, 1 H), 7.47 (br d, -8.3 Hz, 1
H), 8.16 (d, 5.6 Hz, 1 H), 12.75
(br s, 1 H); LC-MS: MH' = 371.
Example 10
5-Difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylthio]-1
H-benzimidazole
Starting from 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridinyl)methylthio]-
1 H-benzimidazole
mono hydrate (28.6 g, 73.4 mmol) and methanol-d2 (10.0 g, 294 mmol), the
procedure described
under Example 9 was followed to give 5-difluoromethoxy-2-[(3-methoxy-4-
dideuteriomethoxy-2-
pyridinyl)methylthio]-1 H-benzimidazole as a water-wet brownish solid; yield
46.4 g, KF = 51.6% (82%).
'H-NMR (400 MHz, DMSO-d6): S= 3.81 (s, 3H), 3.86 (s, 1 H), 4.67 (s, 2H), 6.97
(dd, 8.4 Hz, 2.0 Hz,
1 H), 7.08 (d, 5.5 Hz, 1 H), 7.16 (t, 74.7 Hz, 1 H), 7.21-7.53 (br m, 2H),
8.16 (d, 5.5 Hz, 1 H), 12.78 (br s,
1 H); LC-MS: MH' = 370.
Example 11
5-Difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl )methylthio]-
1 H-benzimidazole
Starting from 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridinyl)methylthio]-
1 H-benzimidazole
mono hydrate (29.5 g, 75.6 mmol) and methanol-d1 (10.0 g, 303 mmol), the
procedure described
under Example 9 was followed to give 5-difluoromethoxy-2-[(3-methoxy-4-
monodeuteriomethoxy-2-
pyridinyl)methylthio]-1 H-benzimidazole as a water-wet brownish solid; yield
50.3 g, KF = 50.8% (89%).
'H-NMR (200 MHz, DMSO-d6): 8= 3.82 (s, 3H), 3.88 (s, 2H), 4.67 (s, 2H), 6.98
(dd, 8.6 Hz, 2.2 Hz,
1 H), 7.08 (d, 5.6 Hz, 1 H), 7.15 (t, 74.8 Hz, 1 H), 7.22-7.53 (br m, 2H),
8.16 (d, 5.6 Hz, 1 H), 12.79 (br s,
1 H); LC-MS: MH' = 369.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
19
Example 12
5-Difluoromethoxy-2-[(4-methoxy-3-trideuteriomethoxy-2-pyridinyl)methylthio]-1
H-benzimidazole
Starting from 5-difluoromethoxy-2-[(4-chloro-3-trideuteriomethoxy-2-
pyridinyl)methylthio]-1 H-
benzimidazole mono hydrate (6.97 g, 17.7 mmol) and methanol (2.28 g, 71.2
mmol), the procedure
described under Example 9 was followed to give 5-difluoromethoxy-2-[(4-methoxy-
3-
trideuteriomethoxy-2-pyridinyl)methylthio]-1l-l-benzimidazole as a water-wet
brownish solid; yield 7.01
g, KF = 19.1% (87%).
1H-NMR (200 MHz, DMSO-d6): S= 3.89 (s, 3H), 4.68 (s, 2H), 6.97 (dd, 8.6 Hz,
2.0 Hz, 1 H), 7.08 (d,
5.5 Hz, 1 H), 7.16 (t, 74.7 Hz, 1 H), 7.18-7.47 (br m, 2H), 8.16 (d, 5.6 Hz, 1
H), 12.76 (br s, 1 H); LC-MS:
MH'=371.
Example 13
5-Difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylthio]-1 H-
benzimidazole
At 50-55 C, a 2-chloromethyl-3,4-bis(trideuteriomethoxy)pyridinium chloride
(15.4 g, 66.8 mmol) was
added portionwise over 30 min to a mixture of 5-difluoromethoxy-1l-l-
benzimidazole-2-thiol (14.5 g,
66.8 mmol), ethanol (133 mL), and 2M aqueous NaOH (73.5 mL, 147 mmol).
Stirring at 50-55 C was
continued for 1-2 h before ethanol was removed by distillation under vacuum at
40 C. The remaining
aqueous emulsion was diluted with water (50 mL) and extracted three times with
dichloromethane (165
mL portions). The combined organic phase was washed with 0.1 M aqueous NaOH
(165 mL), dried
over Na2SO4, and evaporated to dryness to give 5-difluoromethoxy-2-[(3,4-
bis(trideuteriomethoxy)-2-
pyridinyl)methylthio]-1 H-benzimidazole as a brown oil; yield 23.8 g (95%).
Example 14
rac-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl
)methylsulfinyl]-1 l-1-
benzimidazole - large scale procedure
At 25-35 C, aqueous sodium hypochlorite (10.5 kg at 10% strength, 14.2 mol)
was added over 3-4 h
to a solution of 5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylthio]-1 H-
benzimidazole (10.4 kg, KF = 49.7%, 14.2 mol) and 40% aqueous NaOH (2.84 kg)
in a mixture of wa-
ter (49 L) and isopropanol (49 L). Stirring at 25-35 C was continued for 0.5-
1 h before the reaction
was quenched by addition of 1% aqueous Na2S203 (4.3 L). Then, about 65 L of
solvents were distilled
off at 30-45 C under vacuum. After dilution with water (55 L), another
portion of solvents (8-10 L) was
removed by distillation. While keeping the reaction mixture at 40-45 C, 10%
aqueous acetic acid (-13
L) was added over 1.5 h until pH 8.5-9.5 was reached. Once crystallization had
set in, the pH was
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
slowly adjusted to 6.8-7.2 by addition of more 10% aqueous acetic acid (-0.6
L). After cooling to 20-25
C, crude product was filtered off and washed with water (7.5 L) and re-
dissolved in a mixture of water
(80 L), 40% aqueous NaOH (1.6 L) and Na2S2O3 (60 g). The resulting slightly
turbid aqueous solution
was washed twice with MIBK (12 L each) and cleared by Hyflo treatment (0.40
kg), before the pH was
adjusted to 9.0-9.5 by addition of 10% aqueous acetic acid (-8 L) at 40-45 C.
Once product started to
crystallize, further 10% acetic acid was added so as to continuously maintain
a pH of 9.0-9.5. Finally,
centrifugation at 20-25 C including an aqueous rinse (7.5 L) and drying in
vacuo at about 50 C gave
rac-5-difl uoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-benzimidazole
as an off-white solid (m. p. = 134-135 C, decomp.); yield 3.59 kg (65%).
'H-NMR (400 MHz, DMSO-d6): S= 3.78 (s, 3H), 4.67 (d, 13.1 Hz, 1 H), 4.73 (d,
13.1 Hz, 1 H), 7.10 (d,
5.5 Hz, 1 H), 7.18 (br d, 8.7 Hz, 1 H), 7.24 (t, 74.4 Hz, 1 H), 7.44 (br s, 1
H), 7.70 (br s, 1 H), 8.15 (d, 5.5
Hz, 1 H), 13.73 (br s, 1 H); LC-MS: MH' = 387.
Example 15
rao-5-Difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl
)methylsulfinyl]-1 l-1-
benzimidazole
Starting from wet 5-difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-
pyridinyl)methylthio]-1 H-
benzimidazole (32.7 g, KF = 51.6%, 42.8 mmol) and following the procedure
described under Example
14, rac-5-difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole was obtained as an off-white solid (m. p. = 133-135 C,
decomp.); yield 10.8 g (65%).
1H-NMR (200 MHz, DMSO-d6): S= 3.32 (br s, NH + H20), 3.77 (s, 3H), 3.86 (s, 1
H), 4.65 (d, 13.1 Hz,
1 H), 4.73 (d, 13.1 Hz, 1 H), 7.10 (d, 5.5 Hz, 1 H), 7.15 (dd, 8.8 Hz, 2.4 Hz,
1 H), 7.23 (t, 74.4 Hz, 1 H),
7.44 (d, 2.2 Hz, 1 H), 7.69 (d, 8.8 Hz, 1 H), 8.15 (d, 5.5 Hz, 1 H); LC-MS:
MH' = 386.
Example 16
rac-5-Difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole
Starting from wet 5-difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-
pyridinyl)methylthio]-1 H-
benzimidazole (34.8 g, KF = 50.8%, 46.5 mmol) and following the procedure
described under Example
14, rac-5-difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 l-1-
benzimidazole was obtained as an off-white solid (m. p. = 134-135 C,
decomp.); yield 14.0 g (78%).
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
21
'H-NMR (200 MHz, DMSO-d6): S= 3.78 (s, 3H), 3.88 (s, 2H), 4.66 (d, 13.2 Hz, 1
H), 4.73 (d, 13.1 Hz,
1 H), 7.10 (d, 5.6 Hz, 1 H), 7.16 (dd, 8.8 Hz, 2.4 Hz, 1 H), 7.24 (t, 74.4 Hz,
1 H), 7.45 (d, 2.2 Hz, 1 H), 7.69
(d, 8.8 Hz, 1 H), 8.15 (d, 5.5 Hz, 1 H), 13.77 (br s, 1 H); LC-MS: MH' = 385.
Example 17
rac-5-Difluoromethoxy-2-[(4-methoxy-3-trideuteriomethoxy-2-pyridinyl
)methylsulfinyl]-1 l-1-
benzimidazole
Starting from wet 5-difluoromethoxy-2-[(4-methoxy-3-trideuteriomethoxy-2-
pyridinyl)methylthio]-1 H-
benzimidazole (3.00 g, KF = 19.1%, 6.55 mmol) and following the procedure
described under Example
38, rao-5-difluoromethoxy-2-[(4-methoxy-3-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole was obtained, after crystallization from TBME (10 mL); as an off-
white solid (m. p. _
133-134 C, decomp.); yield 1.83 g (72%).
'H-NMR (200 MHz, DMSO-d6): S= 3.90 (s, 3H), 4.66 (d, 13.1 Hz, 1 H), 4.73 (d,
13.1 Hz, 1 H), 7.10 (d,
5.6 Hz, 1 H), 7.15 (dd, 8.9 Hz, 2.4 Hz, 1 H), 7.24 (t, 74.4 Hz, 1 H), 7.45 (d,
2.1 Hz, 1 H), 7.69 (d, 8.8 Hz,
1 H), 8.15 (d, 5.5 Hz, 1 H), 13.77 (br s, 1 H); LC-MS: MH' = 387.
Example 18
rac-5-Difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-
pyridinyl)methylsulfinyl]-1 H-benzimidazole
Starting from 5-difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-
pyridinyl)methylthio]-1 H-
benzimidazole (23.8 g, 63.7 mmol) and following the procedure described under
Example 38, rao-5-
difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl )methylsulfinyl]-1
H-benzimidazole was
obtained, after crystallization from diisopropyl ether (700 mL), as an off-
white solid; yield 20.9 g (84%).
Example 19
rac-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl
)methylsulfinyl]-1 l-1-
benzimidazole sodium salt mono hydrate
At 15-30 C, 40 % aqueous NaOH (0.85 kg, 8.50 mol) was added over 10-30 min to
a solution of rao-5-
difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-
1 H-benzimidazole (3.29
kg, 8.51 mol) in acetone (18 L). The resulting suspension was heated at 50-55
C until a clear solution
was obtained. Crystallization of product was achieved by slow cooling to 10-15
C over about 12 h.
The solids were filtered off and washed with acetone (1.7 L) before being re-
crystallized from ace-
tone/water 32:1 (19 L). Finally, drying at 50 C in vacuo gave rac-5-
difluoromethoxy-2-[(3-methoxy-4-
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
22
trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole sodium salt
mono hydrate as an off-
white solid (m. p. = 151-152 C (decomp.), KF = 4.3 %); yield 2.93 kg (81%).
'H-NMR (200 MHz, DMSO-d6): S= 3.78 (s, 3H), 4.34 (d, 12.9 Hz, 1 H), 4.68 (d,
12.9 Hz, 1 H), 6.72 (dd,
8.6 Hz, 2.4 Hz, 1 H), 7.02 (t, 75.8 Hz, 1 H), 7.07 (d, 5.6 Hz, 1 H), 7.24 (d,
2.2 Hz, 1 H), 7.44 (d, 8.6 Hz,
1 H), 8.22 (d, 5.5 Hz, 1 H); LC-MS: MNa' = 409, MH' = 387.
Example 20
rac-5-Difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl
)methylsulfinyl]-1 l-1-
benzimidazole sodium salt mono hydrate
Starting from rac-5-difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole (8.10 g, 21.0 mmol), the procedure described under Example 19
gave rac-5-
difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylsulfinyl]-
1 H-benzimidazole
sodium salt mono hydrate as an off-white solid (m. p. = 150-152 C (decomp.),
KF = 4.8 %); yield 6.05
g (68%).
'H-NMR (200 MHz, DMSO-d6): S= 3.77 (s, 3H), 3.85 (s, 1 H), 4.36 (d, 12.9 Hz, 1
H), 4.66 (d, 12.9 Hz,
1 H), 6.73 (dd, 8.6 Hz, 2.4 Hz, 1 H), 7.02 (t, 75.8 Hz, 1 H), 7.07 (d, 5.6 Hz,
1 H), 7.25 (d, 2.3 Hz, 1 H), 7.45
(d, 8.6 Hz, 1 H), 8.22 (d, 5.5 Hz, 1 H); LC-MS: MNa' = 408, MH' = 386.
Example 21
rao-5-Difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole sodium salt mono hydrate
Starting from rac-5-difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-
pyridinyl)methylsulfinyl]-
1 H-benzimidazole (10.2 g, 26.5 mmol), the procedure described under Example
19 gave rao-5-
difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-benzimidazole
sodium salt mono hydrate as an off-white solid (m. p. = 151-152 C (decomp.),
KF = 4.1 %); yield 8.95
g (79%).
'H-NMR (200 MHz, DMSO-d6): S= 3.78 (s, 3H), 3.88 (s, 2H), 4.34 (d, 12.9 Hz, 1
H), 4.68 (d, 12.9 Hz,
1 H), 6.73 (dd, 8.6 Hz, 2.4 Hz, 1 H), 7.03 (t, 75.8 Hz, 1 H), 7.08 (d, 5.5 Hz,
1 H), 7.24 (d, 2.2 Hz, 1 H), 7.44
(d, 8.6 Hz, 1 H), 8.22 (d, 5.5 Hz, 1 H); LC-MS: MNa' = 407, MH' = 385.
Example 22
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
23
rac-5-Difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-
pyridinyl)methylsulfinyl]-1 H-benzimidazole
sodium salt mono hydrate
At 15-25 C, 6M aqueous NaOH (8.92 mL, 53.5 mmol) was added over about 15 min
to a solution of
rac-5-difl uoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-
pyridinyl)methylsulfinyl]-1 H-benzimidazole
(21.0 g, 53.9 mmol) in a 6:1 mixture of ethanol/dichloromethane (725 mL).
After stirring for another 10
min at room temperature, most of the solvents were distilled off. The
resulting concentrate (115 g) was
diluted with diisopropyl ether (1.7 L). Some dark waxy residue remained
undissolved, and the super-
natant clear yellow solution was decanted off. To this solution, another
portion of diisopropyl ether (3.4
L) was added to effect precipitation of product. The suspension was cooled to
0 C, and the solids
were filtered off, washed with diisopropyl ether (100 mL) and dried at 40 c
in vacuo to give rao-5-
Difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1
H-benzimidazole sodium
salt mono hydrate as an off-white solid (KF = 4.0 %); yield 18.9 g (82%).
'H-NMR (400 MHz, DMSO-d6): S= 4.32 (d, 12.9 Hz, 1 H), 4.70 (d, 12.9 Hz, 1 H),
6.72 (dd, 8.6 Hz, 2.4
Hz, 1 H), 7.04 (t, 75.8 Hz, 1 H), 7.08 (d, 5.5 Hz, 1 H), 7.23 (d, 2.4 Hz, 1
H), 7.44 (d, 8.6 Hz, 1 H), 8.22 (d,
5.5 Hz, 1 H); LC-MS: MNa' = 412, MH' = 390.
Example 23
rac-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl
)methylsulfinyl]-1 l-1-
benzimidazole sodium salt sesqui hydrate
At 48-55 C, rao-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1l-1-
benzimidazole sodium salt mono hydrate (2.93 kg, 6.87 mol) was dissolved in a
mixture of isopropanol
(12 L) and water (0.50 L). After treatment with Hyflo Super Cel (56 g) and
cooling to 18-25 C, crystalli-
zation was accomplished by seeding with an authentic sample of product
followed by stirring for 40 h
at 18-25 c and another 5 h at 10-15 C. Centrifugation and drying at 45 C in
vacuo gave rao-5-
difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-
1 H-benzimidazole so-
dium salt sesqui hydrate as a white solid (m. p. = 140-142 C (decomp.), KF =
6.6%); yield 2.28 kg
(78%).
Example 24
Bis-[rac-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole] magnesium salt di hydrate
At 40 C, a solution of rac-5-difluoromethoxy-2-[(3-methoxy-4-
trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-benzimidazole sodium salt (500 mg, KF = 4.3 %,
1.17 mmol) in water (10.0
mL) was subjected to a clean filtration. After cooling to room temperature, a
solution of anhydrous
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
24
magnesium chloride (61.4 mg, 0.644 mmol) in 1.0 mL of water was added. The
resulting suspension
was stirred at room temperature for an additional 18 h before being cooled to
0 C and filtered. The
filter cake was re-pulped in water (7.5 mL), filtered, rinsed with water (5.0
mL) and dried at 40 C in
vacuo to give bis-[rac-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-
1 H-benzimidazole] magnesium salt di hydrate as a white solid (m. p. 180-182
C (decomp.); KF =
4.7%; HPLC: 99.5% a/a); yield 369 mg (76 %).
Example 25
(S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole - large scale procedure for undried starting material
At room temperature, 382 g of wet 5-difluoromethoxy-2-[(3-methoxy-4-
trideuteriomethoxy-2-
pyridinyl)methylthio]-1 H-benzimidazole (KF = 47.6%, 0.540 mol) were suspended
in 2.44 L of methyl
isobutyl ketone together with (+)-L-tartaric acid bis-(N-pyrrolidinamide)
(55.0 g). The mixture was
heated to 40 C and about 1.25 L of solvent were evaporated under vacuum to
remove water. Then,
zirconium (IV) n-propoxide (24.0 mL, 70 % in n-propanol) was added and
stirring at 40 C was contin-
ued for one more hour. After cooling to 30 C, N-ethyldiisopropylamine (6.5
mL) and cumene hydrop-
eroxide (103 mL, -80% strength) were added. After stirring for about 18 h at
30 C, TLC indicated no
further conversion of starting material. The clear reaction mixture was
diluted with 500 mL of methyl
isobutyl ketone and quenched with 7.0 g of sodium thiosulphate in 800 mL of
saturated sodium bicar-
bonate solution. After phase separation, the organic layer was washed twice
with 400 mL of saturated
sodium bicarbonate solution. To the organic phase, 1.5 L of water were added,
and the pH was ad-
justed to pH = 13 using 40 % aqueous sodium hydroxide. The organic layer was
extracted with another
400 mL of water at pH 13. After treatment with Hyflo Super Cel (5.0 g), the pH
of the combined aque-
ous phase is adjusted to about 9 by addition of 10% aqueous acetic acid at 40 -
45 C. Once precipita-
tion of product had set in, the mixture was stirred for another 12 h with
eventual readjustment of the
pH. Crude product (160 g, 75% yield) with an optical purity of > 98 % was
obtained by filtration includ-
ing an aqueous rinse (200 mL).
To further increase the purity, crude product was dissolved in dichloromethane
(2.0 L) and washed
with water (400 mL). Crystallization was achieved by a solvent chase with TBME
(final volume about
1.1 L). The crystals were filtered off at about 0 C, washed with TBME (400
mL), and dried at 30 C in
vacuo to give (S)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole as an off-white solid (m. p. 146-148 C (decomp.); KF = 0.8%);
yield 135 g (64 %).
Chiral HPLC: > 98.0% ee; optical rotation: [a]o =-98 (MeOH, c = 0.50).
'H-NMR (200 MHz, DMSO-d6): S= 3.41 (br s, NH + H20), 3.77 (s, 3H), 4.65 (d,
13.0 Hz, 1 H), 4.73 (d,
13.1 Hz, 1 H), 7.09 (d, 5.6 Hz, 1 H), 7.15 (dd, 8.9 Hz, 2.4 Hz, 1 H), 7.23 (t,
74.4 Hz, 1 H), 7.44 (d, 2.1 Hz,
1 H), 7.68 (d, 8.9 Hz, 1 H), 8.14 (d, 5.5 Hz, 1 H); LC-MS: MH' = 387.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
Example 26
(R)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole
Starting from 5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylthio]-1 H-
benzimidazole (70.7 g, KF = 47.6%, 100 mmol) and using (-)-D-tartaric acid bis-
(N-pyrrolidinamide)
(10.3 g, 40.0 mmol) as chiral ligand, the procedure described under Example 25
gave, after
recrystallizatiion from TBME, (R)-5-difluoromethoxy-2-[(3-methoxy-4-
trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-benzimidazole as an off-white solid (m. p. 140-
142 C (decomp.); KF =
0.8%); yield 22.2 g (57 %).
Chiral HPLC: > 98.0% ee; optical rotation: [a]o =+97 (MeOH, c = 0.50).
1H-NMR (200 MHz, DMSO-d6): S= 3.77 (s, 3H), 4.65 (d, 13.2 Hz, 1 H), 4.73 (d,
13.1 Hz, 1 H), 7.09 (d,
5.5 Hz, 1 H), 7.16 (br d, - 10.3 Hz, 1 H), 7.23 (t, 74.4 Hz, 1 H), 7.44 (br s,
1 H), 7.68 (br s, 1 H), 8.14 (d,
5.5 Hz, 1 H), 13.73 (br s, 1 H); LC-MS: MH' = 387.
Example 27
(S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole sodium salt
At room temperature, to a suspension of (S)-5-difluoromethoxy-2-[(3-methoxy-4-
trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-benzimidazole (100 g, 0.259 mol) in a mixture of
methyl isobutyl ketone
(750 mL), isopropanol (75 mL), and water (5.0 mL) was added 40% aqueous NaOH
(18.1 mL, 259
mmol). After heating to 50 c a clear solution was obtained, which was
subjected to treatment with
Hyflo Super Cel (10.0 g). Crystallization of product set in upon cooling to
room temperature and was
driven to completion by further cooling to 0 C. Finally, the crystals were
filtered off, washed with
methyl isobutyl ketone (3 portions, 40 mL each) and dried at 35 C in vacuo to
give (S)-5-
difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-
1 H-benzimidazole so-
dium salt as a white hygroscopic solid (m. p. 105-106 C (decomp.); KF =
10.3%); yield 105 g (89 %).
Chiral HPLC: > 99.0% ee; optical rotation: [a]o =-94 (MeOH, c = 0.50).
Example 28
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
26
(R)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole sodium salt
Starting from (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole (15.5 g, 40.1 mmol) and following the procedure described under
Example 27, (R)-5-
difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-
1 H-benzimidazole so-
dium salt was obtained as a white hygroscopic solid (m. p. 98-103 C
(decomp.); KF = 11.3%); yield
17.4 g (94 %).
Chiral HPLC: > 98.0% ee; optical rotation: [a]o =+91 (MeOH, c = 0.50).
Example 29
Bis-[(S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole] magnesium salt tri hydrate
Starting from (S)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole sodium salt (500 mg, KF = 10.3 %, 1.10 mmol) and following the
procedure described
under Example 24, bis-[(S)-5-difluoromethoxy-2-[(3-methoxy-4-
trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-benzimidazole] magnesium salt tri hydrate was
obtained as a white solid
(m. p. 169-175 C (decomp.); KF = 6.4%); yield 350 mg (75 %).
Chiral HPLC: > 99.0% ee; optical rotation: [a]o =-122 (MeOH, c = 0.50).
Example 30
Bis-[(R)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole] magnesium salt tri hydrate
Starting from (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole sodium salt (2.30 g, KF = 11.3 %, 5.00 mmol) and following the
procedure described
under Example 24, bis-[(R)-5-difluoromethoxy-2-[(3-methoxy-4-
trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-benzimidazole] magnesium salt tri hydrate was
obtained as a white solid
(m. p. 141-145 C (decomp.); KF = 6.9%); yield 1.23 g (58 %).
Chiral HPLC: > 99.0% ee; optical rotation: [a]o =+120 (MeOH, c = 0.50).
Example 31
Synthesis of starting material 5-trideuteriomethoxy-1 H-benzimidazole-2-thiol
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
27
Preparation of 4-trideuteriomethoxy-nitrobenzene
To a solution of sodium hydroxide (15.6 g, 390 mmol) in a mixture of methanol-
d4 (47.4 mL, 1.17 mol)
and THF (50 mL) was added a solution of 1-fluoro-4-nitrobenzene (50.0 g, 354
mmol) in THF (200 mL)
over 2 h at 15-25 C. The resulting suspension was stirred for 3 more h at
room temperature before
10% aqueous HCI (100 mL) and toluene (150 mL) were added. The organic phase
was separated and
evaporated to dryness to give 4-trideuteriomethoxy-nitrobenzene as a brown
oil, which crystallized
upon standing (m. p. 48-51 C); yield 56.6 g (quantitative).
'H-NMR (200 MHz, DMSO-d6): 8= 7.15 (m, 2H), 8.22 (m, 2H); GC-MS: M' = 156.
Preparation of 4-trideuteriomethoxy-acetanilide
An autoclave was charged with 10% Pd/C (3.6 g, water wet), 4-
trideuteriomethoxy-nitrobenzene (72.5
g, 464 mmol) and isopropanol (508 mL). After thorough purging with nitrogen (4
times), the resulting
mixture was stirred under hydrogen pressure (3-4 bar) at 50-60 C until the
uptake of hydrogen
stopped (about 2.5 h). The reaction mixture was cooled to room temperature and
acetic anhydride
(62.5 mL, 580 mmol) was added. Stirring was continued for 4 more h before the
catalyst was filtered
off and washed with hot 2-propanol (270 mL, about 60 C). The combined
filtrates were concentrated
under vacuum to about 150 mL, methylcyclohexane (350 mL) was added, and the
resulting slurry was
cooled to 10 C. Filtration and drying at 45 C in vacuo gave 4-
trideuteriomethoxy-acetanilide as a
grayish solid (m. p. 125-127 C); yield 67.0 g (86 %).
1H-NMR (200 MHz, DMSO-d6): S= 2.00 (s, 3H), 6.85 (m, 2H), 7.47 (m, 2H), 9.74
(br s, 1 H); LC-MS:
MH' = 169.
Preparation of 2-nitro-4-trideuteriomethoxy-aniline
At 10-15 C, 50% aqueous nitric acid (63.0 mL, 654 mmol) was added over 1,5 h
to a solution of 4-
trideuteriomethoxy-acetanilide (50.0 g, 297 mmol) in acetic acid (175 mL).
Stirring was continued for
18 h at room temperature. Then, 20% aqueous NaOH (671 mL) was added over about
1 h at 15-20 C.
The resulting brown suspension was heated at 50 C for 20 h before the pH was
adjusted to about 8
by addition of 20% aqueous HCI (49 mL). Crude product was obtained by cooling
to 10 C and filtra-
tion. After an aqueous rinse, the filter cake was slurried at 60 C in
isopropanol (200 mL) and water
(300 mL) was added over 1 h. While maintaining the temperature between 50 and
60 C, 190 mL of
solvents were distilled off. The resulting suspension was cooled to 10 C,
filtered and washed with
water (60 mL) to provide after drying at 30 C in vacuo 2-nitro-4-
trideuteriomethoxy-aniline as a red
solid (m. p. 120-122 C); yield 46.7 g (92%).
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
28
'H-NMR (200 MHz, DMSO-d6): S= 7.00 (d, 9.3 Hz, 1 H), 7.16 (dd, 9.3 Hz, 2.9 Hz,
1 H), 7.24 (br s, 2H),
7.37 (d, 2.9 Hz, 1 H); GC-MS: M' = 171.
Preparation of 5-trideuteriomethoxy-1 H-benzimidazole-2-thiol
An autoclave was charged with 10% Pd/C (2.23 g, water wet), 2-nitro-4-
trideuteriomethoxy-acetanilide
(45.6 g, 267 mmol) and isopropanol (460 mL). After thorough purging with
nitrogen (4 times), the re-
sulting mixture was stirred under hydrogen pressure (3-4 bar) at 40-50 C
until the uptake of hydrogen
stopped (about 6 h). Then, O-ethylxanthic acid potassium salt (51.2 g, 319
mmol) was added and the
reaction mixture was heated at reflux for 23 h. Water (340 mL) was added and
the pH was adjusted to
12.5 with 20 % aqueous NaOH (10 mL) before roughly the amount of isopropanol
(460 mL) was dis-
tilled off. The resulting dark suspension was treated with charcoal (10 g),
cleared by filtration and
washed with toluene (350 mL). Product was precipitated by addition of 20%
aqueous HCI (53 mL) and
isolated by filtration at 0 C. Rinsing with water (100 mL) and drying at 35 c
in vacuo finally gave 5-
trideuteriomethoxy-1l-l-benzimidazole-2-thiol as an off-white solid (m. p. 247-
250 C); yield 45.5 g (93
%).
'H-NMR (400 MHz, DMSO-d6): S= 6.67 (d, 2.3 Hz, 1 H), 6.72 (dd, 8.7 Hz, 2.4 Hz,
1 H), 7.03 (d, 8.6 Hz,
1 H), 12.36 (br s, 1 H), 12.40 (br s, 1 H); LC-MS: MH' = 184.
Example 32
Synthesis of starting material 4-chloro-2-chloromethyl-3,5-dimethylpyridinium
chloride
Preparation of 4-chloro-2-hydroxymethyl-3,5-dimethylpyridine
At 90-95 C, a solution of 4-chloro-2,3,5-trimethylpyridine-N-oxide (60.0 g,
350 mmol) in toluene (920
mL), which was kept at about 60 C, was added over 7 h to acetic anhydride
(232 mL). Under vacuum
at about 60 C, the reaction mixture was concentrated until 820 mL had been
distilled off. Toluene (840
mL) was added and, again, solvents were distilled off (940 mL). Then, toluene
(180 mL) and 40%
aqueous NaOH (80 mL) were added before the reaction mixture was heated at 50
C for about 15 h.
After addition of saturated aqueous sodium bicarbonate (120 mL), the phases
were separated and the
aqueous layer was extracted once more with toluene (80 mL). Finally, the
combined organic phase
was washed with saturated aqueous sodium bicarbonate (120 mL) and evaporated
to dryness to give
4-chloro-2-hydroxymethyl-3,5-dimethylpyridine as a brownish oil which
solidified upon standing; yield
61.8 g (quantitative).
'H-NMR (200 MHz, DMSO-d6): S= 2.30 (s, 3H), 2.36 (s, 3H), 4.58 (br s, 2H),
5.11 (br s, 1 H), 8.27 (s,
1 H); LC-MS: MH' = 172/174.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
29
Preparation of 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride
To a solution of 4-chloro-2-hydroxymethyl-3,5-dimethylpyridine (60.7 g, 354
mmol) and DMF (0.25 mL,
3.54 mmol) in toluene (200 mL) was added thionyl chloride (26.9 mL, 371 mmol)
over 2 h at 15-30 C.
After stirring for 2 more h at ambient temperature, ethanol (6 mL) was added
to the thick slurry. The
solids were filtered off at about 10 C, washed with toluene (80 mL) and dried
at 40 C in vacuo to give
4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride as an off-white solid
(m. p. 195-196 C); yield
66.5 g (84%).
'H-NMR (200 MHz, DMSO-d6): S= 2.36 (s, 3H), 2.46 (s, 3H), 4.93 (s, 2H), 8.44
(s, 1 H), 8.79 (br s,
1 H); LC-MS: MH' = 190/192/194.
Example 33
5-Trideuteriomethoxy-2-[(4-chloro-3,5-dimethyl-2-pyridinyl )methylthio]-1 H-
benzimidazole
At 55-65 C, a solution of 4-chloro-2-chloromethyl-3,5-dimethylpyridinium
chloride (12.6 g, 55.6 mmol)
in water (21 mL) was added over 2 h to a mixture of 5-trideuteriomethoxy-1 H-
benzimidazole-2-thiol
(9.50 g, 51.8 mmol), toluene (47 mL), water (23 mL) and 40% aqueous NaOH (14
mL). Stirring at 60
C was continued for 16 h before the reaction mixture was cooled to about 10
C. The precipitate was
filtered off, washed with toluene (17 mL) and re-pulped in water (132 mL).
Filtration followed by an
aqueous rinse (70 mL) and drying at 35 C in vacuo gave 5-trideuteriomethoxy-2-
[(4-chloro-3,5-
dimethyl-2-pyridinyl)methylthio]-1 H-benzimidazole mono hydrate (KF = 5.0%) as
an off-white solid (m.
p. 99-102 C); yield 15.1 g (82%).
'H-NMR (200 MHz, DMSO-d6): 8= 2.30 (s, 3H), 2.43 (s, 3H), 4.72 (s, 2H), 6.76
(dd, 8.7 Hz, 2.5 Hz,
1 H), 6.97 (br s, 1 H), 7.35 (d, 8.7 Hz, 1 H), 8.28 (s, 1 H), 12.47 (br s, 1
H); LC-MS: MH' = 337/339.
Example 34
5-Methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridinyl)methylthio]-1 H-benzimidazole
Starting from 5-methoxy-1l-l-benzimidazole-2-thiol (24.0 g, 111 mmol) and
following the procedure
described under Example 33, 5-methoxy-2-[(4-chloro-3,5-dimethyl-2-
pyridinyl)methylthio]-1 l-1-
benzimidazole mono hydrate (KF = 5.2%) was obtained as an off-white solid (m.
p. 100-102 C); yield
34.8 g (89%).
'H-NMR (200 MHz, DMSO-d6): 8= 2.30 (s, 3H), 2.43 (s, 3H), 4.72 (s, 2H), 6.76
(dd, 8.7 Hz, 2.5 Hz,
1 H), 6.98 (br s, 1 H), 7.35 (d, 8.7 Hz, 1 H), 8.28 (s, 1 H), 12.41 (br s, 1
H); LC-MS: MH' = 334/336.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
Example 35
5-Trideuteriomethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl )methylthio]-1 H-
benzimidazole
At 60-65 C, to a solution of 5-trideuteriomethoxy-2-[(4-chloro-3,5-dimethyl-2-
pyridinyl)methylthio]-1 H-
benzimidazole mono hydrate (5.20 g, 14.7 mmol) in NMP (30 mL) was added over
1.5 h solid sodium
methoxide (5.80 g, 104 mmol) in about 10 equal portions. Stirring at 60 C was
continued for 16 h, then
the reaction mixture was heated at 70 C for 24 h and, finally, at 80 C for 4
h. After dilution with water
(200 mL) and addition of 10% aqueous HCI (10 mL), the resulting dark brown
solution was extracted
twice with toluene (100 + 40 mL). The combined organic phase was washed
successively with 5%
aqueous NaOH (2 x 200 mL) and water (100 mL) before being evaporated to
dryness. The residue
was taken up in hot toluene (50 mL), subjected to a clear filtration and,
again, evaporated to dryness.
Finally, crystallization from TBME/toluene 10:1 (33 mL) yielded 5-
trideuteriomethoxy-2-[(4-methoxy-
3,5-dimethyl-2-pyridinyl)methylthio]-1l-l-benzimidazole as a white solid (m.
p. 120-121 C); yield 2.27 g
(46%).
1H-NMR (200 MHz, DMSO-d6): 8= 2.20 (s, 3H), 2.27 (s, 3H), 3.73 (s, 3H), 4.65
(s, 2H), 6.75 (dd, 8.7
Hz, 2.5 Hz, 1 H), 6.97 (br s, 1 H), 7.35 (d, 8.7 Hz, 1 H), 8.17 (s, 1 H),
12.44 (br s, 1 H); LC-MS: MH' _
333.
Example 36
5-Trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-
pyridinyl)methylthio]-1 H-benzimidazole
A solution of sodium trideuteriomethoxid was prepared by addition of methanol-
d4 (1.70 mL, 41.5
mmol) at about 50 C over 30 min to a suspension of sodium hydride (60% in
mineral oil, 1.70 g, 41.5
mmol) in NMP (12 mL). After heating to 60 C, a solution of 5-
trideuteriomethoxy-2-[(4-chloro-3,5-
dimethyl-2-pyridinyl)methylthio]-1l-l-benzimidazole mono hydrate (2.10 g, 5.92
mmol) in NMP (4 mL)
was added. Stirring was continued, first at 70 C for 24 h, then at 85 C for
5 h. Following the work-up
procedure described under Example 35, 5-trideuteriomethoxy-2-[(3,5-dimethyl-4-
trideuteriomethoxy-2-
pyridinyl)methylthio]-1 H-benzimidazole was obtained as a white solid (m. p.
120-121 C); yield 0.55 g
(28%).
1H-NMR (200 MHz, DMSO-d6): 8= 2.20 (s, 3H), 2.27 (s, 3H), 4.64 (s, 2H), 6.75
(dd, 8.7 Hz, 2.4 Hz,
1 H), 6.89-7.38 (br m, 2H), 8.17 (s, 1 H), 12.42 (br s, 1 H); LC-MS: MH' =
336.
Example 37
5-Methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl )methylthio]-1 H-
benzimidazole
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
31
Starting from 5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridinyl)methylthio]-1 H-
benzimidazole mono
hydrate (24.0 g, 68.2 mmol) and following the procedure described under
Example 36, 5-methoxy-2-
[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H-benzimidazole
was obtained as a white
solid (m. p. 119-121 C); yield 8.72 g (38%).
'H-NMR (200 MHz, DMSO-d6): 8= 2.20 (s, 3H), 2.27 (s, 3H), 3.77 (s, 3H), 4.64
(s, 2H), 6.75 (dd, 8.7
Hz, 2.5 Hz, 1 H), 6.98 (br s, 1 H), 7.35 (br d, 8.6 Hz, 1 H), 8.17 (s, 1 H),
12.43 (br s, 1 H); LC-MS: MH' _
333.
Example 38
rao-5-Trideuteriomethoxy-2-[(4-methoxy-3,5-dimethyl-2-
pyridinyl)methylsulfinyl]-1 H-benzimidazole
5-Trideuteriomethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylthio]-1 H-
benzimidazole (1.50 g,
4.51 mmol) was dissolved in CH2CI2 (15 mL) and cooled to -55 to -40 C. At
this temperature, a solu-
tion of 3-chloroperoxybenzoic acid (wet, 77% strength, 1.12 g, 5.00 mmol) in
CH2CI2 (8 mL) was slowly
added over 1.5 h. After one more h at -55 to -40 C, triethylamine (0.87 mL,
6.28 mmol) and a 1:1
mixture of 6% aqueous Na2CO3 and 2% aqueous Na2S203 (10 mL) were successively
added while
allowing the mixture to warm to about 0 C. Stirring was continued for 1 h at
ambient temperature. The
phases were separated, and the organic layer was washed twice with a 1:1
mixture of 6% aqueous
Na2CO3 and 2% aqueous Na2S203 and once with water (10 mL each) before being
evaporated to dry-
ness. The resulting residue was crystallized from ethyl acetate (6.0 mL) to
give rac-5-
trideuteriomethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1l-l-
benzimidazole as a white
solid (m. p. 150-152 C, decomp.); yield 1.27 g(81 %).
1H-NMR (200 MHz, DMSO-d6): S= 2.17 (s, 3H), 2.20 (s, 3H), 3.69 (s, 3H), 4.67
(d, 13.6 Hz, 1 H), 4.77
(d, 13.5 Hz, 1 H), 6.92 (dd, 8.9 Hz, 2.4 Hz, 1 H), 7.09 (br s, 1 H), 7,54 (br
d, 8.9 Hz, 1 H), 8.18 (s, 1 H),
13.39 (br s, 1 H); LC-MS: MH' = 349.
Example 39
rac-5-Trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 l-1-
benzimidazole
Starting from 5-trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-
pyridinyl)methylthio]-1 H-
benzimidazole (1.20 g, 3.57 mmol) and following the procedure described under
Example 38, rac-5-
trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl
)methylsulfinyl]-1 H-benzimidazole
was obtained as a white solid (m. p. 147-148 C, decomp.); yield 0.90 g (72%).
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
32
'H-NMR (200 MHz, DMSO-d6): S= 2.16 (s, 3H), 2.20 (s, 3H), 4.67 (d, 13.5 Hz, 1
H), 4.77 (d, 13.5 Hz,
1 H), 6.90-7.55 (br m, 3H), 8.18 (s, 1 H), 13.39 (br s, 1 H); LC-MS: MH' =
352.
Example 40
rac-5-Methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl
)methylsulfinyl]-1 H-benzimidazole
Starting from 5-methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-
pyridinyl)methylthio]-1 H-
benzimidazole (1.00 g, 3.01 mmol) and following the procedure described under
Example 38, rac-5-
methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-
benzimidazole was
obtained as a white solid (m. p. 143-144 C, decomp.); yield 0.86 g (82%).
'H-NMR (200 MHz, DMSO-d6): S= 2.17 (s, 3H), 2.20 (s, 3H), 3.81 (s, 3H), 4.67
(d, 13.6 Hz, 1 H), 4.77
(d, 13.5 Hz, 1 H), 6.90-7.55 (br m, 3H), 8.18 (s, 1 H), 13.40 (br s, 1 H); LC-
MS: MH' = 349.
Example 41
(S)-5-Trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-
benzimidazole sodium salt
At room temperature, 5-trideuteriomethoxy-2-[(3,5-dimethyl-4-
trideuteriomethoxy-2-
pyridinyl)methylthio]-1 H-benzimidazole (3.02 g, 9.00 mmol) and (+)-L-tartaric
acid bis-(N-
pyrrolidinamide) (0.92 g, 3.60 mmol) were suspended in 35 mL of methyl
isobutyl ketone. The mixture
was heated to 40 C and about 8 mL of solvent were evaporated under vacuum to
remove water.
Then, zirconium (IV) n-propoxide (0.40 mL, 70 % in n-propanol, 0.90 mmol) was
added and stirring at
40 C was continued for one more hour. After cooling to 30 C, N-
ethyldiisopropylamine (0.11 mL, 0.63
mmol) and cumene hydroperoxide (1.52 mL, -80% strength, 8.55 mmol) were added.
After stirring for
about 20 h at 30 C, the clear reaction mixture was diluted with methyl
isobutyl ketone (8.5 mL) and
quenched with sodium thiosulphate (0.11 g) in saturated sodium bicarbonate
solution (15 mL). After
phase separation, the organic layer was washed twice with saturated sodium
bicarbonate solution (7.5
mL each). To the organic phase, water was added (25 mL), and the pH was
adjusted to pH = 12.5-13
using 40 % aqueous NaOH (0.71 mL). The organic layer was extracted twice more
with water (7.5 mL)
at pH 12.5-13 (through addition of prerequisite amount of 40% aqueous NaOH).
The combined organic
phase was washed with dichloromethane (15 mL). Then, the pH was adjusted to
about 10 with potas-
sium dihydrogen phosphate and the aqueous solution was extracted with
dichloromethane (once 40
mL and twice 10 mL). Evaporation of the organic phase to dryness gave (S)-5-
trideuteriomethoxy-2-
[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-
benzimidazole as a brownish oil,
which was further purified by formation of the corresponding sodium salt.
To this end, the crude product was taken up in methyl isobutyl ketone (15 mL)
and isopropanol (1.5
mL). Then, 40% aqueous NaOH (0.63 mL) was added and the resulting suspension
wsa cooled to 0
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
33
C. The solids were filtered off, washed with methyl isobutyl ketone (twice 2.0
mL) and dried at 45 C in
vacuo to give (S)-5-trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-
1 H-benzimidazole sodium salt as an off-white solid (m. p. 224-225 C
(decomp.), KF = 1.5%); yield
2.05 g (61 %).
Chiral HPLC: > 97.0% ee; optical rotation: [a]o =-44 (MeOH, c = 0.53), [a]o
=+39 (H2O, c = 0.39).
1H-NMR (200 MHz, DMSO-d6): S= 2.18 (s, 3H), 2.21 (s, 3H), 4.39 (d, 12.9 Hz, 1
H), 4.63 (d, 12.9 Hz,
1 H), 6.54 (dd, 8.7 Hz, 2.5 Hz, 1 H), 6.98 (d, 2.5 Hz, 1 H), 7,32 (br d, 8.6
Hz, 1 H), 8.23 (s, 1 H).
Example 42
Bis-[(S)-5-trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 l-1-
benzimidazole] magnesium salt
Starting from (S)-5-trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-
1 H-benzimidazole sodium salt (200 mg, KF = 1.5 %, 0.528 mmol) and following
the procedure
described under Example 24, bis-[(S)-5-trideuteriomethoxy-2-[(3,5-dimethyl-4-
trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1l-l-benzimidazole] magnesium salt was obtained as a
white solid (m. p. 161-
162 C (decomp.); KF = 1.5%); yield 132 mg (68 %).
Chiral HPLC: > 97.0% ee; optical rotation: [a]o =-120 (MeOH, c = 0.50).
By proper combination of the procedures described above, further compounds of
general formula (1)
are also accessible:
For example, 4-chloro-2-chloromethyl-3-methylpyridinium chloride could be
reacted with 1 l-1-
benzimidazole-2-thiol according to the procedure described under Example 7 to
give 2-[(4-chloro-3-
methyl-2-pyridinyl)methylthio]-1l-l-benzimidazole. Conversion of this product
with, for instance, 1,1-
dideuterio-3-methoxy-l-propanol or 1,1-dideuterio-2,2,2-trifluoroethanol
following the protocol de-
scribed under Example 9 would then give rise to formation of 2-[(4-(1,1-
dideuterio-3-methoxyprop-1-
oxy)-3-methyl-2-pyridinyl)methylthio]-1 H-benzimidazole and 2-[(4-(1,1-
dideuterio-2,2,2-trifluoroethoxy)-
3-methyl-2-pyridinyl)methylthio]-1l-l-benzimidazole, respectively. Finally,
oxidation of these compounds
according to the procedure used in Example 38 would provide rao-2-[(4-(1,1-
dideuterio-3-
methoxypropan-1-oxy)-3-methyl-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole
and rac-2-[(4-(1,1-
dideuterio-2,2,2-trifluoroethoxy)-3-methyl-2-pyridinyl)methylsulfinyl]-1 H-
benzimidazole, respectively,
both of which represent compounds of formula (1).
As a further example, 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride
could be reacted with 5-
methoxy-1 H-imidazo[4,5-b]pyridine-2-thiol according to the procedure
described under Example 33 to
give 5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridinyl)methylthio]-1 H-
imidazo[4,5-b]pyridine. Conversion
of this product with methanol-d4 following the protocol described under
Example 36 would then give
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
34
rise to formation of 5-methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-
pyridinyl)methylthio]-1 H-
imidazo[4,5-b]pyridine, which, in turn, could be oxidized according to the
procedure used in Example
38 to rao-5-methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-
pyridinyl)methylsulfinyl]-1 H-imidazo[4,5-
b]pyridine, that is, another compound of formula (1).
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
Commercial utility
The compounds of the general formula 1 and their salts and solvates,
preferably hydrates, and the
solvates, preferably hydrates of the salts (hereinafter "compounds of the
invention") have useful phar-
macological properties, rendering them commercially utilizable. In particular,
they have a pronounced
inhibitory effect on the secretion of gastric acid and excellent
gastrointestinal protective action in warm-
blooded animals, in particular man. Here, the compounds according to the
invention are distinguished
by a highly selective action, an advantageous duration of action, a
particularly high bioavailability, a
metabolisation profile that is uniform among different individuals, the lack
of significant side-effects and
a wide therapeutic spectrum.
In this context, "gastrointestinal protection" is to be understood as the
prevention and treatment of gas-
trointestinal disorders, in particular gastrointestinal inflammatory disorders
and lesions (such as, for
example, Ulcus ventriculi, Ulcus duodeni, gastritis, irritable bowel owing to
an increased production of
acid or as a result of pharmaceutical compositions, GERD, Crohn's disease,
IBD) which may be
caused, for example, by microorganisms (for example Helicobacter pylori),
bacterial toxins, pharma-
ceutical compositions (for example certain antiphlogistics and antirheumatic
drugs), chemicals (for
example ethanol), gastric acid or stress.
With their excellent properties, the compounds according to the invention, in
various models for the
determination of antiulcerogenic and antisecretory properties, surprisingly
prove to be clearly superior
to the prior art compounds, in particular with respect to their
pharmacokinetic properties. These im-
proved pharmacokinetic properties allow for example a reduction of the amount
of a compound accord-
ing to the invention, which is needed for treatment or prophylaxis. Or by
using the same amount of the
compound according to the invention as done for the prior art compounds a
longer duration of action
may be achieved. Related with these properties are advantages concerning
patient safety or economi-
cal aspects, e.g. like drug costs etc.. Owing to these properties, the
compounds according to the inven-
tion are highly suitable for use in human and veterinary medicine, where they
are used, in particular,
for the treatment and/or prophylaxis of gastrointestinal disorders.
Accordingly, the invention furthermore provides the use of the compounds
according to the invention
for the treatment and/or prophylaxis of the abovementioned diseases.
The invention also embraces the use of the compounds according to the
invention for preparing phar-
maceutical compositions used for the treatment and/or prophylaxis of the
abovementioned diseases.
The invention also provides pharmaceutical compositions comprising the
compounds according to the
invention. In particular, the invention provides pharmaceutical compositions
for oral use in solid form,
containing the compounds of formulae 1, 1 a or 1 b in the form of their salts,
in particular in the form of a
sodium or magnesium salt, and/or in the form of a hydrate of such salt.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
36
The pharmaceutical compositions are prepared by processes known per se which
are familiar to the
person skilled in the art. As pharmaceutical compositions, the compounds
according to the invention
are employed either as such or, preferably, in combination with suitable
pharmaceutical auxiliaries or
carriers in the form of tablets, coated tablets, capsules, suppositories,
plasters (for example as TTS),
emulsions, suspensions or solutions, where the content of active compound is
advantageously from
about 0.1 to about 95% and where it is possible to produce pharmaceutical
dosage forms (for example
flow-release forms or enteric forms) which, by the appropriate choice of
auxiliaries and carriers, are
tailored for the active compound and/or the desired onset of action and/or the
duration of action.
The auxiliaries or carriers suitable for the desired pharmaceutical
formulations are known to the person
skilled in the art. In addition to solvents, gel formers, suppository bases,
tabletting auxiliaries and other
carriers for active compounds, it is possible to use, for example,
antioxidants, dispersants, emulsifiers,
antifoams, flavour-masking agents, preservatives, solubilizers, colorants or,
in particular, permeation
promoters and complex formers (for example cyclodextrins).
The compounds according to the invention can be administered orally,
parenterally or percutaneously.
In human medicine, it has generally been found to be advantageous to
administer the compounds
according to the invention, when given orally, in a daily dose of from about
0.01 to about 1, preferably
about 0.02 to about 0.5 and in particular about 0.04 to about 0.3, mg/kg of
body weight [calculated on
the basis of the compounds according to the invention in free form, i. e. not
in salt form (= "free com-
pound"], if appropriate in the form of a plurality of, preferably 1 to 4,
individual doses, to obtain the de-
sired result. For parenteral treatment, it is possible to use similar or (in
particular when the active com-
pounds are administered intravenously) generally lower dosages. The optimum
dosage and the type of
administration of the active compounds required in each case can easily be
determined by the person
skilled in the art.
A further aspect of the invention is thus a pharmaceutical composition,
comprising one or more com-
pound according to the invention together with one or more customary
auxiliaries, where the single
dose comprises from about 2 to about 60 mg of the free compound.
A further aspect of the invention is a pharmaceutical composition, comprising
one or more compound
according to the invention together with one or more customary auxiliaries,
where the single dose com-
prises from about 4 to about 40 mg of the free compound.
A further aspect of the invention is the use of the compounds according to the
invention for treating
gastrointestinal disorders.
A further aspect of the invention is the use of the compounds according to the
invention for treating
gastrointestinal disorders in patients who are slow metabolizers.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
37
A further aspect of the invention is the use of the compounds according to the
invention hereof for
treating gastrointestinal disorders in patients who have a risk of drug
interactions.
A further aspect of the invention is the use of the compounds according to the
invention for treating
gastrointestinal disorders in patients who need an inhibition of acid
secretion for an extended period of
time.
A further aspect of the invention is a pharmaceutical composition for treating
gastrointestinal disorders
for use in patients who are slow metabolizers, comprising one or more compound
according to the
invention together with one or more customary auxiliaries, where the single
dose comprises from about
2 to about 60 mg of free compound.
A further aspect of the invention is a pharmaceutical composition for treating
gastrointestinal disorders
for use in patients who are slow metabolizers, comprising one or more compound
according to the
invention together with one or more customary auxiliaries, where the single
dose comprises from about
4 to about 40 mg of free compound.
A further aspect of the invention is a pharmaceutical composition for treating
gastrointestinal disorders
for use in patients who have a risk of drug interactions, comprising one or
more compound according
to the invention together with one or more customary auxiliaries, where the
single dose comprises from
about 2 to about 60 mg of free compound.
A further aspect of the invention is a pharmaceutical composition for treating
gastrointestinal disorders
for use in patients who have a risk of drug interactions, comprising one or
more compound according
to the invention together with one or more customary auxiliaries, where the
single dose comprises from
about 4 to about 40 mg of free compound.
A further aspect of the invention is a pharmaceutical composition for treating
gastrointestinal disorders
for use in patients who need an inhibition of acid secretion for an extended
period of time, comprising
one or more compound according to the invention together with one or more
customary auxiliaries,
where the single dose comprises from about 2 to about 60 mg of free compound.
A further aspect of the invention is a pharmaceutical composition for treating
gastrointestinal disorders
for use in patients who need an inhibition of acid secretion for an extended
period of time, comprising
one or more compound according to the invention together with one or more
customary auxiliaries,
where the single dose comprises from about 4 to about 40 mg of free compound.
A further aspect of the invention is a pharmaceutical composition for treating
gastrointestinal disorders
for use in patients who are slow metabolizers, comprising in an oral solid
application form one or more
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
38
salt according to the invention or a hydrate thereof together with one or more
customary auxiliaries,
where the single dose comprises from about 2 to about 60 mg of free compound.
A further aspect of the invention is a pharmaceutical composition for treating
gastrointestinal disorders
for use in patients who are slow metabolizers, comprising in an oral solid
application form one or more
salt according to the invention or a hydrate thereof together with one or more
customary auxiliaries,
where the single dose comprises from about 4 to about 40 mg of free compound.
A further aspect of the invention is a pharmaceutical composition for treating
gastrointestinal disorders
for use in patients who have a risk for drug interactions, comprising in an
oral solid application form
one or more salt according to the invention or a hydrate thereof together with
one or more customary
auxiliaries, where the single dose comprises from about 2 to about 60 mg of
free compound.
A further aspect of the invention is a pharmaceutical composition for treating
gastrointestinal disorders
for use in patients who have a risk for drug interactions, comprising in an
oral solid application form
one or more salt according to the invention or a hydrate thereof together with
one or more customary
auxiliaries, where the single dose comprises from about 4 to about 40 mg of
free compound.
A further aspect of the invention is a pharmaceutical composition for treating
gastrointestinal disorders
for use in patients who need an inhibition of acid secretion for an extended
period of time, comprising
in an oral solid application form one or more salt according to the invention
or a hydrate thereof to-
gether with one or more customary auxiliaries, where the single dose comprises
from about 2 to about
60 mg of free compound.
A further aspect of the invention is a pharmaceutical composition for treating
gastrointestinal disorders
for use in patients who need an inhibition of acid secretion for an extended
period of time, comprising
in an oral solid application form one or more salt according to the invention
or a hydrate thereof to-
gether with one or more customary auxiliaries, where the single dose comprises
from about 4 to about
40 mg of free compound.
If the compounds according to the invention are to be used for treating the
abovementioned diseases,
the pharmaceutical preparations may also comprise one or more
pharmacologically active ingredients
from other groups of pharmaceutical compositions. Examples that may be
mentioned include tranquil-
izers (for example from the group of the benzodiazepines, e. g., diazepam),
spasmolytic drugs (e. g.,
bietamiverine or camylofine), anticholinergic drugs (e. g., oxyphencyclimine
or phencarbamide), local
anesthetics (e. g., tetracaine or procaine), and optionally also enzymes,
vitamins or amino acids.
In this context, particular emphasis is given to the combination of the
compounds according to the in-
vention with other pharmaceuticals which buffer or neutralize gastric acid or
which inhibit the secretion
of acid, such as, for example, antacids (such as, for example, magaldrate) or
H2 blockers (e.g., ci-
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
39
metidine, ranitidine), and with gastrin antagonists with the aim to enhance
the main action in an addi-
tive or superadditive sense and/or to eliminate or reduce side-effects or to
obtain a more rapid onset of
action. Mention may also be made of the fixed or free combination with NSAIDs
(such as, for example,
etofenamate, diclofenac, indometacin, ibuprofen or piroxicam) for preventing
the gastrointestinal dam-
age caused by the NSAIDs, or with compounds, which modify gastrointestinal
motility, or with com-
pounds, which reduce the incidence of transient lower esophageal sphincter
relaxation (TLOSR), or
with antibacterial substances (such as, for example, cephalosporins,
tetracyclins, penicillins, mac-
rolides, nitroimidazoles or else bismuth salt) for controlling Helicobacter
pylori. Antibacterial combina-
tion partners that may be mentioned include, for example, mezlocillin,
ampicillin, amoxicillin, cefalothin,
cefoxitin, cefotaxim, imipenem, gentamycin, amicacin, erythromycin,
ciprofloxacin, metronidazole,
clarithromycin, azithromycin and combinations thereof (e.g., clarithromycin +
metronidazole or amox-
icillin + clarithromycin).
In practicing the present invention, the compounds according to this invention
may be administered in
combination therapy separately, sequentially, simultaneously or
chronologically staggered (such as
e.g. as combined unit dosage forms, as separate unit dosage forms, as adjacent
discrete unit dosage
forms, as fixed or non-fixed combinations, as kit-of-parts or as admixtures)
with one or more standard
therapeutics as those mentioned above.
The term "combination" according to this invention may be present as a fixed
combination, a non-fixed
combination or a kit-of-parts.
A "fixed combination" is defined as a combination wherein a first active
ingredient and a second active
ingredient are present together in one unit dosage or in a single entity. One
example of a "fixed combi-
nation" is a pharmaceutical composition wherein the said first active
ingredient and the said second
active ingredient are present in admixture of simultaneous administration,
such as in a formulation.
Another example of a "fixed combination" is a pharmaceutical composition
wherein the said first active
ingredient and the said second active ingredient are present in one unit
without being in admixture.
A "kit-of-parts" is defined as a combination wherein the said first active
ingredient and the said second
active ingredient are present in more than one unit. One example of a "kit-of-
parts" is a combination
the said first active ingredient and the said second active ingredient are
present separately. The com-
ponents of the kit-of-parts may be administered separately, sequentially,
simultaneously or chronologi-
cally staggered.
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
Pharmacology
Metabolisation in liver microsomes
Materials and methods
Pantoprazole or examples 1 or 2 (10 pM each) were incubated with liver
microsomes (source: all from
GenTest except Mini Pig from TEBU ),incubation in 1 mg/ml protein, 100 mM Tris-
HCI, pH 7.4, 1 mM
NADPH2). Reaction was terminated after 90 minutes by liquid nitrogen, the
parent compound was de-
tected by HPLC (10 mM KH2PO4, pH 7.4, acetonitril gradient 20-44 %).
Tablel:
Metabolism of H-pantoprazole versus deutero-compounds (example 1, 2) with
microsomes after 90
minutes incubation time (species dependent).
Species Percent of compound metabolized
H-Pantoprazole Example 1 Example 2 Example 1/ Example 2/
Pantoprazole Pantoprazole
Rat 61 35 17 0,57 0,28
Dog 20 12 10 0,60 0,50
Human 28 14 15 0,50 0,54
Mouse 62 36 17 0,58 0,27
Guinee pig 78 59 54 0,75 0,69
Monkey 73 47 35 0,64 0,48
Mini Pig 26 19 19 0,73 0,73
Metabolic clearance
In order to evaluate the properties of the compounds according to the
invention the compounds' intrin-
sic clearances in recombinant human cytochrome P450 (CYP) isoenzymes CYP1A2,
CYP2C8,
CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were determined.
Materials and methods
Compounds as described in examples 17, 19, 20, 21, 27, 28, 38, 39, 40 and 41
and the non-
deuterated racemic omeprazole, its (S)-enantiomer and non-deuterated
pantoprazole and its enanti-
omers were incubated in a buffer containing 1 nmol/mL recombinant P450 (Cypex,
Dundee, UK),
4 mg/mL microsomal protein, 100 mMol/L Tris-HCI (pH 7.4) and 1 mMol/L NADPH
for 0, 3, 6, 12, and
15 or 30 minutes at 37 C. Incubations were carried out in triplicate. For
incubations with CYP2C19 the
P450 concentration was lowered to 0.5 nmol/mL and the incubation interval
changed to 0, 1, 2, 3, 4,
and 5 min. The intrinsic clearance was determined based on the rate of
disappearance of parent com-
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
41
pound. Omeprazole and the deuterated analogues were determined by HPLC-UV. The
lower limit of
assay resolution based on experimental variability was 17.6 pl/min/nmol P450.
Results
CYP2C19 and CYP3A4 were found to contribute to the oxidative metabolism of
omeprazole, pantopra-
zole and their deuterated analogues. All other cytochrome P450 isoenzymes
(CYP1A2, CYP2C8,
CYP2C9, CYP2D6, CYP3A5) did not contribute to the metabolism of any of the
compounds investiga-
ted above the lower limit of assay resolution.
Formation kinetics of omeprazole 5-hydroxy-omeprazole and 5-(difluoromethoxy)-
2-ff(3-
methoxy-4-sulfate-2-gyridyl)-methyllsulfinyll-1 H-benzimidazole
Following the evaluation of the metabolic clearance of the compounds according
to the invention via
P450 enzymes, the formation kinetics of the main metabolite identified in
humans, i.e. 5-hydroxy-
omeprazole (5-methoxy-2[[(4-methoxy-3-methyl-5-hydroxymethyl-2-pyridinyl)-
methyl]sulfinyl]-1 H-
benzimidazole) for omeprazole and 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfate-
2-pyridyl)-
methyl]sulfinyl]-1 H-benzimidazole for pantoprazole was determined. The
generation of 5-hydroxy-
omeprazole and 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)-
methyl]sulfinyl]-1 H-
benzimidazole is predominantly carried out by CYP2C19. We chose pooled human
cryopreserved
hepatocytes as the more advanced in vitro system compared to human liver
microsomes, because all
major drug metabolizing enzymes (phase I, phase II, hydrolases) are functional
in this in vitro system.
Materials and methods
Compounds as described in examples 17, 19, 20, 21, 27, 28, 38, 39, 40 and 41
and the non-
deuterated racemic omeprazole, its (S)-enantiomer and non-deuterated
pantoprazole and its enanti-
omers were incubated in Krebs Henseleit Puffer (KHB), containing 84 pg/mL
amikacin, 1 mMol/L cal-
cium chloride, 20 mMol/L Hepes, 4.2 pMol/L hepatonic acid, 28.5 mMol/L sodium
bicarbonate, and
human cryopreserved hepatocytes (10 donor pool, InVitro Technologies,
Baltimore, MD USA) at a
concentration of 106 cells/mL. 5-hydroxy-omeprazole and 5-(difluoromethoxy)-2-
[[(3-methoxy-4-sulfate-
2-pyridyl)-methyl]sulfinyl]-1 H-benzimidazole (M2) formation rates under these
conditions were linear up
to 60 min. The 5-hydroxy-omeprazole formation rate was determined at ten
different compound con-
centrations (0, 1.0, 2.5, 5.0, 10.0, 25.0, 50.0, 100, 200 and 2500 pMol/L)
incubated in duplicate for
60 min at 37 C. The 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)-
methyl]sulfinyl]-1 H-
benzimidazole (M2) formation rate was determined at nine different compound
concentrations (0, 0.5,
1.0, 2.5, 5.0, 10.0, 25.0, 50.0 and 100 pMol/L) incubated in duplicate for 60
min at 37 C. 5-hydroxy-
omeprazole was quantified using LC-MS/MS. 5-hydroxy-omeprazole obtained from
Ramidius AB,
Lund, Sweden and 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)-
methyl]sulfinyl]-1 H-
benzimidazole (M2) isolated from human urine were used as an external
standard. The concentration
to reach the half-maximal formation rate (KM-value) and the maximal formation
rate (Vmex) were obtai-
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
42
ned by non-linear regression analysis using the Michaelis-Menten equation. The
intrinsic clearance
(CI;,,,) was obtained dividing Vn,,~, over KM.
Results
Examples 39 and 40, both deuterated in the 4-methoxy-pyridinyl position
exhibited formation rates that
were about 1.5-fold reduced compared to non-deuterated omeprazole. There was
no difference be-
tween the KM-values of racemic ['H], [2H3], and [2H6] omeprazole analogues
that exceeded experimen-
tal variability (Figure 1). Reduction in the 5-hydroxy-omeprazole formation
rate was observed for ex-
ample 40, but was surprisingly not found for example 38 (Figure 1). Moreover,
there was no difference
in the formation rate between [2H3]omeprazole deuterated in the 4-methoxy-
pyridinyl position (example
40) and [2H6]omeprazole additionally deuterated in the 5-methoxy-benzimidazole
position (example 41,
Figure 3).The formation of 5-hydroxy-omeprazole from rac. ['H]omeprazole and
its (S)-enantiomer
exhibited stereospecific differences, since the difference between the KM and
Vn,,~, values of racemic
and (S)-omeprazole exceeded experimental variability. The substitution of six
[1H] atoms by [2H] atoms
in the 4-methoxy-pyridinyl and 5-methoxy-benzimidazole position of (S)-
omeprazole (example 41), did
not alter the intrinsic clearance (Cl;,,t) of 5-hydroxy-omeprazole (Figure 3).
The formation of 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)-
methyl]sulfinyl]-1 H-
benzimidazole (M2) from pantoprazole, its enantiomers and from compounds as
described in exam-
ples 17, 19, 20, 21, 27 and 28 appeared to be inhibited by substrate
concentrations above 100 pM.
Therefore, the data for incubations with 100 and 250 pM substrate
concentrations were excluded from
the calculation of Kn, and Vn,,, The formation of M2 from racemic
['H]pantoprazole and enantiomers
exhibited stereospecific differences (Figure 2A). Racemic, (R), and (S)-
analogues (examples 19,
27and 28 deuterated in the 4-methoxy-pyridyl position exhibited formation
rates that were at least
2.5-fold reduced compared to their non-deuterated counterparts (Figure 2B).
The intrinsic clearances
of racemic, (R), and (S)-analogues deuterated in the 4-methoxy-pyridyl
position (examples 19, 27 and
28) were at least 4.7-fold reduced compared to their non-deuterated
counterparts (Table 2). The
stereospecific differences in M2 formation rates observed for the ['H]
pantoprazole analogues were
less pronounced for analogues deuterated in the 4-methoxy-pyridyl position
(Figure 2B). Surprisingly,
the reduction in M2 formation rate as compared to the non-deuterated compounds
seems to depend-
ent on the position of the trideuteriomethoxy-group in the pyridyl moiety of
the molecule (Figure 4).
Increasing the number of ['H] atoms substituted by [2H] atoms in the 4-methoxy-
pyridyl position of the
molecule ([' H], [2Hj] example 21, [2H2] example 20, and [2H3] example 19)
decreased M2 formation
rates.
Table 2:
CA 02615670 2008-01-17
WO 2007/012650 PCT/EP2006/064666
43
Intrinsic clearance (Cl;,,t)) in pooled human hepatocytes obtained upon
incubation with pantoprazole
and compounds according to the invention.
Compound Clint [ limini106 cells] %E C,iõt rac. omeprazole
rac. omeprazole 2.0 100
Example 40 1.4 69
Example 38 2.1 107
Example 39 1.4 69
(S)-omeprazole sodium 0.7 37
Example 41 0.8 40
% E C,iõt rac. pantoprazole
rac. pantoprazole Na 1.5 H20 27.9 100
Example 19 5.1 18
Example 17 22.0 79
Example 20 13.5 48
Example 21 17.7 63
% E C,iõt (R)-pantoprazole
(R)-pantoprazole Na 1.5 H20 25.7 100
Example 28 5.5 21
% E C,iõt (S)-pantoprazole
(S)-pantoprazole Na 1.5 H20 16.1 100
Example 27 3.4 21
