Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same

Compounds of the formula (Ia) are disclosed by the invention, along with compositions thereof optionally in combination with compounds of formulae (Ib). Methods of making and using the same are also disclosed.

FIELD OF THE INVENTION
 The invention generally relates to novel pharmaceutically active compounds,
 compositions comprising the same, pharmaceutical formulations of the same,
 methods of making the same, and methods of using the same.
 BACKGROUND OF THE INVENTION
 Various compounds used in inhibiting gastric acid secretion are known in
 the art and include a class of benzimidazole-substituted compounds, one of
 which is omeprazole. Omeprazole is currently commercially available in the
 formulation PRILOSEC.RTM.. In particular, U.S. Pat. No. 4,255,431 proposes
 such benzimidazole-substituted compounds generally described by the
 formula (III) in the '431 patent that allegedly encompasses omeprazole.
 Various methods of making these compounds are also proposed in the '431
 patent.
 European Pat. No. 0 124 495 B1 proposes various salts of omeprazole, namely
 alkaline salts of the formula (I) in the '495 reference which includes
 lithium, sodium, potassium, magnesium, and calcium salts, along with
 methods of making the salts. The methods of forming these salts may
 involve employing a hydroxide, alkoxide, or amine base, or cation exchange
 using a metal salt.
 Erlandsson, P., et al. J. Chromatography, 532 (1990) pp. 305-319 propose
 separating the (-) and (+) enantiomers of omeprazole utilizing
 chromatographic techniques. In this publication, the separation is
 proposed to take place on a preparative scale using a cellulose-based
 chiral phase, e.g., trisphenyl-carbamoyl cellulose coated on 3-aminopropyl
 silica. It is appreciated that other schemes and processes are available
 for this separation.
 PCT Publication No. WO 94/27988 proposes salts of the single enantiomers of
 omeprazole and methods of making the same. The process involves separating
 the two stereoisomers of a diastereomer mixture of an
 acyloxymethyl-substituted benzimidazole compound described by the formula
 (IV) set forth in this published application, followed by solvolysis of
 each separated diastereomer in an alkaline solution. Salts of the single
 enantiomers are formed and isolated by neutralizing aqueous solutions of
 the salts of the single enantiomers of omeprazole with a neutralizing
 agent.
 PCT Publication No. WO 96/02535 proposes a process for the enantioselective
 synthesis of single enantiomers of omeprazole or its alkaline salts. The
 process employs an oxidizing agent and a chiral titanium complex which may
 include a titanium(IV) compound.
 PCT Publication No. WO 98/54171 proposes the magnesium salt of the (-)
 enantiomer of omeprazole. The '171 publication also proposes a method of
 synthesizing the above magnesium salt as well as the potassium salt of (-)
 omeprazole that may be used as a suitable intermediate for preparing the
 magnesium salt. The potassium salt is taught to be useful in treating
 gastrointestinal diseases.
 U.S. Pat. No. 5,386,032 to Brandstrom proposes an improved method for
 synthesizing omeprazole which involves reacting
 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl-thio]-1H
 benzimidazole with m-chloroperoxybenzoic acid in a methylene chloride
 solution.
 The teachings regarding the methods of making omeprazole as referred to in
 these references, salts thereof, enantiomers thereof, and salts of the
 enantiomers, as well as formulations which may include these compounds,
 all rely on the chemical structure of omeprazole being accurately
 determined and the referenced compound or compounds being consistently
 prepared using the referenced techniques. More specifically, a methoxy
 group on the benzimidazole ring has been explicitly stated in the
 literature to be present at the 5-position, in omeprazole, a racemic
 mixture, and an optically pure isomer of omeprazole designated as
 esomeprazole or s-omeprazole. Applicants have now unexpectedly discovered
 that the complexity of omeprazole and the intricacies of the bioactivity
 of each of its previously undiscovered attributes has never been
 disclosed. More specifically, Applicants have confirmed that the methods
 of the prior art do not yield a single compound having the methoxy group
 in the 5-position on the benzimidazole ring as previously taught, nor do
 all of the methods of the prior art yield consistent results. In fact,
 omeprazole as conventionally referred to as a bulk drug substance (in its
 solid state) is confirmed to be present in the form of two
 pharmaceutically active compounds having the methoxy group on the
 benzimidazole ring at the 6- and 5-positions. Additionally, Applicants
 have discovered the presence of a second chiral location at the pyridine
 ring plane in each of the two compounds such that each compound has two
 positional isomers and four diastereomers. Therefore, the present
 invention provides these individual compounds, along with any salts,
 hydrates, solvates, combinations thereof, and polymorphs thereof,
 compositions of the above, and methods of making the same which are not
 taught or suggested by the prior art.
 SUMMARY OF THE INVENTION
 The present invention generally provides compounds represented by formula
 (Ia), co-crystallized compositions of compounds represented by formulae
 (Ia) and (Ib), each described in detail herein, one or more
 pharmaceutically acceptable salts, solvates, hydrates, or combinations
 thereof, and complexes thereof. Diastereomers of the above are also
 provided. The invention also provides compositions and pharmaceutical
 formulations of the above. Methods of making the above are also provided
 by the invention.
 More specifically, the present discovery pertains to novel compounds,
 particularly a compound having a methoxy moiety at the 6-position on the
 benzimidazole ring, and compositions comprising compounds having methoxy
 groups at the 5- and 6-positions respectively. It is unexpected and highly
 uncommon that these individual compounds are present in co-crystalline
 form which comprise a single composition. Ratios of the above isomers can
 be manipulated, and novel compounds encompassing a myriad of ratios of
 diastereomers of such compounds are also provided. Each of these is
 described in greater detail hereinafter.
 The invention also provides methods of administering the above compounds
 represented by formula (Ia) and the compositions of compounds represented
 by formulae (Ia) and (Ib) described in detail herein, along with one or
 more optional pharmaceutically acceptable salts, solvates, hydrates,
 complexes, or combinations of these compounds, diastereomers thereof,
 compositions thereof, and pharmaceutically acceptable formulations of the
 above, to a mammal in need of treatment.
 These and other aspects of the invention are set forth in greater detail
 herein.
 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
 The invention is described hereinbelow in greater detail with reference to
 its preferred embodiments. These embodiments, however, are set forth to
 illustrate the invention and are not to be construed as a limitation
 thereof, the invention being defined by the claims.
 In one aspect, the invention relates to a compound represented by the
 formula (Ia) as set forth below. Applicants have unexpectedly discovered
 that this compound, in solid state, has not been taught or suggested by
 the prior art. Additionally, it has been unexpectedly discovered that this
 newly-discovered compound has two distinct chiral locations: (1) a chiral
 center at the sulfoxide group and (2) a chiral plane located at the
 pyridinal moiety of such compound. More specifically, it has been
 furthered discovered that when R.sub.4 is alkoxy, or other appropriate
 substituents, such group is locked into a fixed configuration generally
 perpendicular to the pyridine plane by the steric hindrance of the two
 substituents located in the R.sub.3 and R.sub.5 positions providing
 R.sub.3 and R.sub.5 are not hydrogen. The locked orientation of this
 substituent, preferably methoxy, gives rise to a chiral plane in which
 part or all of such substituent, preferably the methyl substituent of such
 preferred methoxy group, is located either above or below the
 unsymmetrical pyridine chiral plane.
 The compound represented by formula (Ia) is as follows:
 ##STR1##
 wherein:
 S.sub.x represents a chiral sulfur atom comprising at least one of the
 diastereomers represented by S.sub.xa and S.sub.xb, wherein S.sub.xa is
 the (-) enantiomer and S.sub.xb is the (+) enantiomer;
 R is alkoxy;
 R.sub.1 is selected from the group consisting of hydrogen, alkyl, halogen,
 carboalkoxy, alkoxy, and alkanoyl;
 R.sub.2 is hydrogen or alkyl; and
 R.sub.3, R.sub.4, and R.sub.5 may be the same or different and are each
 selected from the group consisting of hydrogen, alkyl, alkoxy, and
 alkoxyalkoxy,
 wherein when R.sub.4 is alkoxy and neither R.sub.3 nor R.sub.5 are not
 hydrogen, the alkyl substituent of such alkoxy group is selected from the
 group consisting of at least one of the enantiomers represented by
 R.sub.4q and R.sub.4z ; wherein R.sub.4q is the (-) enantiomer and lies
 above the chiral plane; and R.sub.4z is the (+) enantiomer and lies below
 the chiral plane;
 or one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof of said compound represented by formula (Ia).
 In one embodiment, all of R.sub.3, R.sub.4, and R.sub.5 are not hydrogen.
 In another embodiment, when two of R.sub.3, R.sub.4, and R.sub.5 are
 hydrogen, the third is not methyl. The compound represented by formula
 (Ia) is preferably present in solid state.
 The term "alkoxy" preferably refers to alkoxy groups having up to 5 carbon
 atoms, preferably up to 3 carbon atoms such as, for example, methoxy,
 ethoxy, n-propoxy, or isopropoxy.
 The term "carboalkoxy" preferably refers to groups having up to 5 carbon
 atoms such as, for example, carbomethoxy, carboethoxy, carbopropoxy, and
 carbobutoxy.
 The term "alkoxyalkoxy" preferably refers to groups having up to 5 carbon
 atoms such as, for example, methoxymethoxy, ethoxyethoxy, and the like.
 Methoxyethoxy is also encompassed under this definition.
 The term "alkyl" preferably refers to alkyl groups having up to 7 carbon
 atoms, more preferably up to 4 carbon atoms, and is thus preferably
 selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl.
 The term "halogen" refers to chloro, bromo, fluoro, or iodo.
 The term "alkanoyl" preferably refers to groups having up to 4 carbon
 atoms. Examples include formyl, acetyl, and propionyl.
 In a preferred embodiment, R is methoxy; R.sub.1 is hydrogen; R.sub.2 is
 hydrogen; R.sub.3 is methyl; R.sub.4 is methoxy; and R.sub.5 is methyl.
 Applicants note that throughout the provisional application upon which
 priority is claimed, the R.sub.1 substituent was referred to as being in
 the 4-position in the compound represented by formula (Ia). For the
 purposes of the present application, the benzimidazole ring is numbered
 such that the R.sub.1 substituent of the compound of formula (Ia) is
 present in the 6-position.
 In various embodiments of the present invention, the compound represented
 by formula (Ia) may be present in the form of various individual
 diastereomers including, for example:
 (a) S.sub.xa --R.sub.4q ;
 (b) S.sub.xa --R.sub.4z ;
 (c) S.sub.xb --R.sub.4q ; and
 (d) S.sub.xb --R.sub.4z,
 or one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof. These descriptions are provided to permit
 differentiation of the various stereoisomers (diastereomers) throughout
 this document, and represent the following in standard chemical
 nomenclature:
 (a) S.sub.xa --R.sub.4q, (S)--(S), or (-)--(-);
 (b) S.sub.xa --R.sub.4z, (S)--(R), or (-)--(+);
 (c) S.sub.xb --R.sub.4q, (R)--(S), or (+)--(-); and
 (d) S.sub.xb --R.sub.4z, (R)--(R), or (+)--(+).
 For the purposes of the invention, the term "enantiomer" as referred to
 herein, refers to diastereomer pairs that are non-superimposable mirror
 images of each other. The term "enantiomeric pair" as referenced herein
 refers to pairs of enantiomers that generate a racemic mixture. Examples
 of enantiomeric pairs include: (1) S--S and R--R and (2) S--R and R--S of
 the compounds of formulae (Ia) and/or (Ib). The term "(-) enantiomer" may
 encompass any of the diastereomers S--S or S--R and pair thereof. The term
 "(+) enantiomer" may encompass any of the diastereomers R--R and R--S and
 pair thereof.
 Preferred embodiments of various species of the compound represented by
 formula (Ia) are represented by the formulae (Iai), (Iaii), (Iaiii), and
 (Iaiv):
 ##STR2##
 wherein S.sub.x is S.sub.xa, or one or more pharmaceutically acceptable
 salts, solvates, hydrates, or combinations thereof of said compound
 represented by formula (Iai);
 ##STR3##
 wherein S.sub.x is S.sub.xa, or one or more pharmaceutically acceptable
 salts, solvates, hydrates, or combinations thereof of said compound
 represented by formula (Iaii);
 ##STR4##
 wherein S.sub.x is S.sub.xb, or one or more pharmaceutically acceptable
 salts, solvates, hydrates, or combinations thereof of said compound
 represented by formula (Iaiii); and
 ##STR5##
 wherein S.sub.x is S.sub.xb, or one or more pharmaceutically acceptable
 salts, solvates, hydrates, or combinations thereof of said compound
 represented by formula (Iaiv).
 The above compounds may be made by various methods including those set
 forth in greater detail herein. Other methods may be also be employed.
 In another aspect, the invention relates to a composition comprising two or
 more compounds represented by the formula (Ia) set forth below. In
 particular, and as discussed in greater detail herein, Applicants provide
 any combination of any of the four diastereomers in varying ratio amounts.
 ##STR6##
 wherein:
 S.sub.x represents a chiral sulfur atom comprising at least one of the
 enantiomer represented by S.sub.xa and S.sub.xb, wherein S.sub.xa is the
 (-) enantiomer and S.sub.xb is the (+) enantiomer;
 R is alkoxy;
 R.sub.1 is selected from the group consisting of hydrogen, alkyl, halogen,
 carboalkoxy, alkoxy, and alkanoyl;
 R.sub.2 is hydrogen or alkyl; and
 R.sub.3, R.sub.4, and R.sub.5 may be the same or different and are each
 selected from the group consisting of hydrogen, alkyl, alkoxy, and
 alkoxyalkoxy,
 wherein when R.sub.4 is alkoxy and neither R.sub.3 nor R.sub.5 are not
 hydrogen, the alkyl substituent of such alkoxy group is selected from the
 group consisting of at least one of the enantiomers represented by
 R.sub.4q and R.sub.4z, wherein R.sub.4q is the (-) enantiomer and lies
 above the chiral plane; and R.sub.4z is the (+) enantiomer and lies below
 the chiral plane;
 or one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof of said compounds represented by formula (Ia).
 The composition of two or more compounds may contain various amounts of the
 enantiomers S.sub.xa, S.sub.xb, R.sub.4q, and R.sub.4z. Methods for making
 the various enantiomers and diastereomers are set forth herein. In one
 embodiment, for example, each of the diastereomers represented by S.sub.xa
 and S.sub.xb in the compounds represented by formula (Ia) is present in a
 range from about 0 percent (w/w) to about 100 percent (w/w) such that the
 total percentage of the sum of S.sub.xa and S.sub.xb equals about 100
 percent (w/w). In another embodiment, each of the enantiomers represented
 by R.sub.4q and R.sub.4z is present in a range from about 0 percent (w/w)
 to about 100 percent (w/w) such that when the total percentage of the sum
 of R.sub.4q and R.sub.4z equals about 100 percent (w/w).
 In the above composition, each of the at least two compounds, may be the
 same or different. Any number of combinations of individual diastereomers
 or combinations thereof of the compound represented by formula (Ia) may be
 present in the composition. Examples of such diastereomers are as follows:
 S.sub.xa --R.sub.4q ; S.sub.xa --R.sub.4z ; S.sub.xb --R.sub.4q ; and
 S.sub.xb --R.sub.4z, or one or more pharmaceutically acceptable salts,
 solvates, hydrates, or combinations thereof of the compound represented by
 formula (Ia).
 In various embodiments, the above diastereomers or combinations thereof may
 be present in such a manner wherein the composition forms a racemic
 mixture. In other embodiments, the diastereomers may be present in such a
 manner wherein the composition does not form a racemic mixture.
 In one embodiment, the diastereomers of each of the compounds represented
 by formula (Ia) in the composition are S.sub.xa --R.sub.4q and S.sub.xb
 --R.sub.4z or one or more pharmaceutically acceptable salts, solvates,
 hydrates, or combinations thereof of the compound represented by formula
 (Ia). These diastereomers may be present in amounts such that the
 composition forms a racemic mixture, or alternatively, these diastereomers
 may be present in amounts such that the composition does not form a
 racemic mixture. In one embodiment, the composition comprising S.sub.xa
 --R.sub.4q and S.sub.xb --R.sub.4z or one or more pharmaceutically
 acceptable salts, solvates, hydrates, or combinations thereof of the
 compound represented by formula (Ia) may be essentially free of compounds
 represented by formula (Ia) having diastereomers S.sub.xa --R.sub.4z and
 S.sub.xb --R.sub.4q. When used in reference to individual diastereomers
 throughout this document, the term "essentially free" means that a
 composition comprising compounds of the present invention having such
 specified diastereomers and diastereomer pairs containing no more than
 about 5 percent concentration of compounds having non-specified
 diastereomers and/or diastereomer pairs, as set forth herein. In one
 embodiment, for example, compounds having these diastereomers (S.sub.xa
 --R.sub.4q and S.sub.xb --R.sub.4z) will form compositions in crystalline
 form which are free or, more typically, essentially free of compounds
 having the diastereomers of S.sub.xa --R.sub.4z and S.sub.xb --R.sub.4q.
 In another embodiment, the diastereomers of each of the compounds
 represented by formula (Ia) in the composition are S.sub.xa --R.sub.4q and
 S.sub.xa --R.sub.4z, or one or more pharmaceutically acceptable salts,
 solvates, hydrates, or combinations thereof of the compound represented by
 formula (Ia). In one example of this embodiment, the above composition is
 essentially free of compounds represented by formula (Ia) having
 diastereomers represented by S.sub.xb --R.sub.4q and/or S.sub.xb
 --R.sub.4z. Typically, this composition is in the form of an oil which,
 using the technique taught hereinafter, may form a crystalline, generally
 a microcrystalline composition. Such a composition may be formed by
 various techniques such as, for example, a lyophilization technique.
 Otherwise, a "salt" of such composition may also be formed independently
 or, preferably, in situ, as described hereinafter.
 In another embodiment, the diastereomers of each of the compounds
 represented by formula (Ia) in the composition are S.sub.xb --R.sub.4z and
 S.sub.xb --R.sub.4q, or one or more pharmaceutically acceptable salts,
 solvates, hydrates, or combinations thereof of the compound represented by
 formula (Ia). In one example of this embodiment, the above composition is
 essentially free of compounds represented by formula (Ia) having
 diastereomers represented by S.sub.xa --R.sub.4z and/or S.sub.xa
 --R.sub.4q. Otherwise, a "salt" of such composition may also be formed
 independently or, preferably, in situ, as described hereinafter.
 In another embodiment, the diastereomers of each of the compounds
 represented by formula (Ia) in the composition is S.sub.xa --R.sub.4q or
 one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof of the compound represented by formula (Ia). In an
 example of this embodiment, the composition is optically pure. The term
 "optically pure" has the meaning generally accepted in the art, and also
 includes given or selected diastereomers and/or diastereomer pairs being
 essentially free of other compounds and/or impurities which would
 substantially affect the optical rotation of the composition. In another
 example of this embodiment, the composition is essentially free of
 compounds represented by the formula (Ia) having diastereomers S.sub.xa
 --R.sub.4z, S.sub.xb --R.sub.4q, and S.sub.xb --R.sub.4z.
 In another embodiment, the diastereomers of each of the compounds
 represented by formula (Ia) in the composition is S.sub.xa --R.sub.4z or
 one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof of the compound represented by formula (Ia). In one
 example of this embodiment, the composition is optically pure as defined
 herein. In another example of this embodiment, the composition is
 essentially free of compounds represented by the formula (Ia) having
 diastereomers S.sub.xa --R.sub.4q, S.sub.xb --R.sub.4q, and S.sub.xb
 --R.sub.4z.
 In another embodiment, the diastereomers of each of the compounds
 represented by formula (Ia) in the composition is S.sub.xb --R.sub.4q or
 one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof of the compound represented by formula (Ia). In an
 example of this embodiment, the composition is optically pure as
 preferably defined herein. In another example of this embodiment, the
 composition is essentially free of compounds represented by the formula
 (Ia) having diastereomers S.sub.xa --R.sub.4q, S.sub.xa --R.sub.4z, and
 S.sub.xb --R.sub.4z.
 In another embodiment, the diastereomers of each of the compounds
 represented by formula (Ia) in the composition is S.sub.xb --R.sub.4z or
 one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof of the compound represented by formula (Ia). In an
 example of this embodiment, the composition is optically pure. In another
 example of this embodiment, the composition is essentially free of
 compounds represented by the formula (Ia) having diastereomers S.sub.xa
 --R.sub.4q, S.sub.xa --R.sub.4z, and S.sub.xb --R.sub.4q.
 Compounds of the present invention comprising each of the individual
 diastereomers represented by S.sub.xa --R.sub.4q ; S.sub.xa --R.sub.4z ;
 S.sub.xb --R.sub.4q ; and S.sub.xb --R.sub.4z may provide significantly
 greater biological activity for the prevention and/or treatment of the
 disease states discussed hereinbelow than components of the present
 invention comprising such compound having the selected diastereomers in
 combination with such compounds having any of the other referenced
 diastereomers.
 Accordingly, methods of the present invention provide for improved
 biological activity/efficacy (e.g. inhibition of gastric acid secretions
 and treatment of gastric acid disturbances in mammals, including humans)
 of pharmaceutically active compounds omeprazole and esomeprazole, as
 presently known in the art, comprising administering to such mammals in
 need of treatment any composition of the present invention comprising
 compounds or compositions of the present invention having an individual
 diastereomers comprising S.sub.xa --R.sub.4q ; S.sub.xa --R.sub.4z ;
 S.sub.xb --R.sub.4q ; or S.sub.xb --R.sub.4z, or one or more
 pharmaceutically acceptable salts, solvates, hydrates, or combinations
 thereof. Also provided are such methods wherein said compounds or
 complexes of the present invention having said selected individual
 diastereomer pair essentially free of compounds of the present invention
 having diastereomer pairs other than said selected individual
 diastereomers. A preferred diastereomer is S.sub.xa --R.sub.4q, and an
 especially preferred diastereomer is S.sub.xa --R.sub.4z.
 In addition, the present invention also provides for improved biological
 activity/efficacy of compositions of the present invention comprising
 compounds or compositions of the present invention having two or more
 diastereomers comprising S.sub.xa --R.sub.4q ; S.sub.xa --R.sub.4z ;
 S.sub.xb --R.sub.4q ; or S.sub.xb --R.sub.4z, comprising administering to
 mammals, including humans, in need of inhibition of gastric acid secretion
 or treatment of gastric acid disturbances any composition of the present
 invention comprising compounds or compositions of the prevent invention
 having an individual diastereomer selected from the group consisting of
 S.sub.xa --R.sub.4q ; S.sub.xa --R.sub.4z ; S.sub.xb --R.sub.4q, or one or
 more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof. Also provided are such methods wherein said
 compounds or complexes of the present invention having said selected
 individual diastereomer essentially free of compounds of the present
 invention having diastereomers other than said selected individual
 diastereomer.
 In any of the above embodiments, each of the two or more compounds
 represented by formula (Ia), which each of said compounds may be the same
 or different, except as otherwise designated, are preferably compounds of
 the formulae represented by (Iai), (Iaii), (Iaiii), or (Iaiv):
 ##STR7##
 wherein S.sub.x is S.sub.xa, or one or more pharmaceutically acceptable
 salts, solvates, hydrates, or combinations thereof of the compound
 represented by formula (Iai);
 ##STR8##
 wherein S.sub.x is S.sub.xa, or one or more pharmaceutically acceptable
 salts, solvates, hydrates, or combinations thereof of the compound
 represented by formula (Iaii);
 ##STR9##
 wherein S.sub.x is S.sub.xb, or one or more pharmaceutically acceptable
 salts, solvates, hydrates, or combinations thereof of the compound
 represented by formula (Iaiii); and
 ##STR10##
 wherein S.sub.x is S.sub.xb, or one or more pharmaceutically acceptable
 salts, solvates, hydrates, or combinations thereof of the compound
 represented by formula (Iaiv). Other species of the compound represented
 by the formula (Ia) may be employed for the purposes of the invention.
 Any of the above embodiments encompassing the compound represented by
 formula (Ia), or one or more pharmaceutically acceptable salts, solvates,
 hydrates, or combinations thereof of the compound and compositions thereof
 may be present in crystalline form.
 In another aspect, the invention also provides a composition of active
 pharmaceutical ingredient ("API") comprising any of the above composition
 embodiments, each of which may be present in crystalline form.
 Advantageously, any of the compositions comprising compounds represented
 by formula (Ia) may also comprise any of the specific compounds
 represented by formulae (Iai), (Iaii), (Iaiii), and (Iaiv), or one or more
 pharmaceutically acceptable salts, solvates, hydrates, polymorphs, or
 combinations thereof whether in crystalline form, amorphous form, or a
 combination thereof, can be used in any such API composition.
 The invention also provides any of the compositions set forth herein
 comprising the two or more compounds of formula (Ia) being essentially
 free of compounds represented by formula (Ib):
 ##STR11##
 wherein:
 S.sub.x represents a chiral sulfur atom comprising at least one of the
 enantiomers represented by S.sub.xa and S.sub.xb, wherein S.sub.xa is the
 (-) enantiomer and S.sub.xb is the (+) enantiomer;
 R is alkoxy;
 R.sub.1 is selected from the group consisting of hydrogen, alkyl, halogen,
 carboalkoxy, alkoxy, and alkanoyl;
 R.sub.2 is hydrogen or alkyl; and
 R.sub.3, R.sub.4, and R.sub.5 may be the same or different and are each
 selected from the group consisting of hydrogen, alkyl, alkoxy, and
 alkoxyalkoxy,
 wherein when R.sub.4 is alkoxy and neither R.sub.3 nor R.sub.5 are
 hydrogen, the alkyl substituent of such alkoxy group is selected from the
 group consisting of at least one of the enantiomers represented by
 R.sub.4q and R.sub.4z ; wherein R.sub.4q is the (-) enantiomer and lies
 above the chiral plane; and R.sub.4z is the (+) enantiomer and lies below
 the chiral plane;
 or one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof of said compounds represented by formula (Ib).
 For the purposes of the invention, the term "pure" refers to a compound of
 the formula (Ia) being present in an amount such that other components are
 present in amounts below limits detectable by conventional technology,
 preferably compound of formula (Ia) being present at least about 97
 percent (w/w) or at least about 98 percent (w/w). The term "essentially
 pure" refers to a compound of the formula (Ia) having trace levels of
 other components (e.g., a compound of formula (Ib), impurities, etc.),
 preferably from about 1 percent to about 4 or about 5 percent of other
 components. As used herein, the term "essentially free of compounds of
 formula (Ib)" refers to the compound represented by formula (Ia)
 preferably being present in an amount which has no more than 5 percent
 (w/w) of such compounds represented by formula (Ib) in such composition.
 In another embodiment, the compound of formula (Ia) may be present in pure
 form, i.e., containing non-detectable or trace amounts of the compound of
 formula (Ib).
 In another aspect, and as discussed in greater detail herein, Applicants
 have discovered that the compounds of formulae (Ia) and (Ib) are typically
 formed in a manner such that they are present in the same crystalline
 lattice, i.e., the compounds co-crystallize from solution. Thus, in this
 aspect, the invention further relates to a composition comprising one
 molecule each of:
 (a) a compound represented by formula (Ia):
 ##STR12##
 wherein:
 S.sub.x represents a chiral sulfur atom comprising at least one of the
 enantiomers represented by S.sub.xa and S.sub.xb, wherein S.sub.xa is the
 (-) enantiomer and S.sub.xb is the (+) enantiomer;
 R is alkoxy;
 R.sub.1 is selected from the group consisting of hydrogen, alkyl, halogen,
 carboalkoxy, alkoxy, and alkanoyl;
 R.sub.2 is hydrogen or alkyl; and
 R.sub.3, R.sub.4, and R.sub.5 may be the same or different and are each
 selected from the group consisting of hydrogen, alkyl, alkoxy, and
 alkoxyalkoxy,
 wherein when R.sub.4 is alkoxy and neither R.sub.3 nor R.sub.5 are
 hydrogen, the alkyl substituent of such alkoxy group is selected from the
 group consisting of at least one of the enantiomer represented by R.sub.4q
 and R.sub.4z, wherein R.sub.4q is the (-) enantiomer and lies above the
 chiral plane; and R.sub.4z is the (+) enantiomer and lies below the chiral
 plane; co-crystallized with:
 (b) a compound represented by formula (Ib):
 ##STR13##
 wherein:
 S.sub.x represents a chiral sulfur atom comprising at least one of the
 enantiomers represented by S.sub.xa and S.sub.xb, wherein S.sub.xa is the
 (-) enantiomer and S.sub.xb is the (+) enantiomer;
 R is alkoxy;
 R.sub.1 is selected from the group consisting of hydrogen, alkyl, halogen,
 carboalkoxy, alkoxy, and alkanoyl;
 R.sub.2 is hydrogen or alkyl; and
 R.sub.3, R.sub.4, and R.sub.5 may be the same or different and are each
 selected from the group consisting of hydrogen, alkyl, alkoxy, and
 alkoxyalkoxy,
 wherein when R.sub.4 is alkoxy and neither R.sub.3 nor R.sub.5 are
 hydrogen, the alkyl substituent of such alkoxy group is selected from the
 group consisting of at least one of the enantiomers represented by
 R.sub.4q and R.sub.4z, wherein R.sub.4q is the (-) enantiomer and lies
 above the chiral plane; and R.sub.4z is the (+) enantiomer and lies below
 the chiral plane;
 wherein R of a compound represented by formula (Ia) and R.sub.1 of a
 compound represented by formula (Ib) each is the same alkoxy substituent;
 and
 each substituent of S.sub.x, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 of a
 compound represented by each of formulae (Ia) and (Ib) are the same;
 or one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof of the composition. The compounds represented by
 formulae (Ia) and (Ib) may be the same or different relative to the
 pyridine enantiomers, but the same for sulfoxide enantiomers.
 Any of the above compositions may include various amounts of the compounds
 represented by formulae (Ia) and (Ib). In different embodiments, for
 example, the composition may comprise the above compounds, which may be
 the same or different, in the following ratios denoted by (a), (b), and
 (c):
 (a) a compound represented by formula (Ia) being present in a range from
 about 1 percent (w/w) to about 99 percent (w/w) and a compound represented
 by formula (Ib) is present in a range from about 1 percent (w/w) to about
 99 percent (w/w) such that the sum of the total percentage of such
 compounds represented by formulae (Ia) and (Ib) equals about 100 percent
 (w/w);
 (b) a compound represented by formula (Ia) being present in a range from
 about 96 percent (w/w) to about 99 percent (w/w) and a compound
 represented by formula (Ib) is present in a range from about 1 percent
 (w/w) to about 4 percent (w/w) such that the sum of the total percentage
 of such compounds represented by formulae (Ia) and (Ib) equals about 100
 percent (w/w); or
 (c) a compound represented by formula (Ia) being present in a range from
 about 1 percent (w/w) to about 91 percent (w/w) and a compound represented
 by formula (Ib) is present in a range from about 9 percent (w/w) to about
 99 percent (w/w) such that the sum of the total percentage of such
 compounds represented by formulae (Ia) and (Ib) equals about 100 percent
 (w/w).
 Each of the above embodiments discussed in (a), (b), or (c) above may
 include various combinations of diastereomers. Such diastereomers are as
 follows: (a) S.sub.xa --R.sub.4q (b) S.sub.xa --R.sub.4z (c) S.sub.xb
 --R.sub.4q or (d) S.sub.xb --R.sub.4z., or one or more pharmaceutically
 acceptable salts, solvates, hydrates, or combinations thereof of the
 compounds represented by formulae (Ia) and (Ib). Any of the above
 composition embodiments may include, for example, compounds of the pairs
 Iai-Ibi, Iaii-Ibii, Iaiii-Ibiii, and Iaiv-Ibiv as follows:
 ##STR14##
 wherein each S.sub.x is S.sub.xa ;
 or one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof of the composition;
 ##STR15##
 wherein each S.sub.x is S.sub.xa ;
 or one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof of the composition;
 ##STR16##
 wherein each S.sub.x is S.sub.xb ;
 or one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof of the composition;
 ##STR17##
 wherein each S.sub.x is S.sub.xb ;
 or one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof of the composition.
 Hereinafter, the compounds (Iai), (Iaii), (Iaiii), (Iaiv), (Ibi), (Ibii),
 (Ibiii), and (Ibiv) are defined by the structures presented above.
 In another aspect, the invention provides a composition comprising two or
 more compounds each of compounds represented by formulae (Ia) and (Ib) as
 described above or one or more pharmaceutically acceptable salts,
 solvates, hydrates, or combinations thereof of the compound represented by
 formulae (Ia) and (Ib). Each of the co-crystals in the composition of
 compounds represented by formulae (Ia) and (Ib), and compounds represented
 by formula (Ia) which are free, or essentially free of compounds
 represented by formula (Ib), if any, may be the same or different.
 The above compositions may include various amounts of the compounds
 represented by formulae (Ia) and (Ib). In different embodiments, for
 example, the composition may comprise the above compounds, which may be
 the same or different, in the following ratios denoted by (a), (b), and
 (c):
 (a) a compound represented by formula (Ia) being present in a range from
 about 1 percent (w/w) to about 99 percent (w/w) and a compound represented
 by formula (Ib) is present in a range from about 1 percent (w/w) to about
 99 percent (w/w) such that the sum of the total percentage of such
 compounds represented by formulae (Ia) and (Ib) equals about 100 percent
 (w/w);
 (b) a compound represented by formula (Ia) being present in a range from
 about 96 percent (w/w) to about 99 percent (w/w) and a compound
 represented by formula (Ib) is present in a range from about 1 percent
 (w/w) to about 4 percent (w/w) such that the sum of the total percentage
 of such compounds represented by formulae (Ia) and (Ib) equals about 100
 percent (w/w); or
 (c) a compound represented by formula (Ia) being present in a range from
 about 1 percent (w/w) to about 91 percent (w/w) and a compound represented
 by formula (Ib) is present in a range from about 9 percent (w/w) to about
 99 percent (w/w) such that the sum of the total percentage of such
 compounds represented by formulae (Ia) and (Ib) equals about 100 percent
 (w/w).
 The above compositions comprising compounds represented by formulae (Ia)
 and (Ib) may advantageously include various percentages of these
 compounds. In one embodiment for example, the percentage of compounds
 represented by formula (Ib) in the composition is less than about 40
 percent (w/w) and the percentage of compounds of formula (Ia) is such that
 the sum of the total percentage of such compounds represented by formulae
 (Ia) and (Ib) is equal to about 100 percent (w/w). In another embodiment,
 the percentage of compounds represented by formula (Ib) in said
 composition is from about 9 percent (w/w) to about 40 percent (w/w) and
 the percentage of compounds of formula (Ia) is such that the sum of the
 total percentage of such compounds represented by formulae (Ia) and (Ib)
 is equal to about 100 percent (w/w).
 The composition of two or more compounds may contain various amounts of the
 enantiomers S.sub.xa, S.sub.xb, R.sub.4q, and R.sub.4z. Methods for making
 the various enantiomers and diastereomers are set forth herein. In one
 embodiment, for example, each of the enantiomers represented by S.sub.xa
 and S.sub.xb in the compounds represented by formula (Ia) is present in a
 range from about 0 percent (w/w) to about 100 percent (w/w) such that the
 total percentage of the sum of S.sub.xa and S.sub.xb equals about 100
 percent (w/w). In another embodiment, each of the enantiomers represented
 by R.sub.4q and R.sub.4z is present in a range from about 0 percent (w/w)
 to about 100 percent (w/w) such that when the total percentage of the sum
 of R.sub.4q and R.sub.4 z equals about 100 percent (w/w).
 In the above composition, each of the at least two compounds, may be the
 same or different. Any number of combinations of individual diastereomers
 or combinations thereof of the compound represented by formula (Ia) may be
 present in the composition. Examples of such diastereomers are as follows:
 S.sub.xa --R.sub.4q ; S.sub.xa --R.sub.4z ; S.sub.xb --R.sub.4q ; and
 S.sub.xb --R.sub.4z, or one or more pharmaceutically acceptable salts,
 solvates, hydrates, or combinations thereof of the compound represented in
 formulae (Ia) and (Ib).
 In various embodiments, the above diastereomers or combinations thereof may
 be present in such a manner wherein the composition forms a racemic
 mixture. In other embodiments, such diastereomers may be present in such a
 manner wherein the composition does not form a racemic mixture.
 In another embodiment, the diastereomers of the compounds represented by
 formulae (Ia) and (Ib) which are present in the above compositions may
 include the following: (a) S.sub.xa --R.sub.4q and (b) S.sub.xb --R.sub.4z
 or one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof of the compounds represented by formulae (Ia) and
 (Ib). In one example of this embodiment, the composition forms a racemic
 mixture. In another example of this embodiment, the composition does not
 form a racemic mixture. In another example of this embodiment, the
 composition is essentially free from compounds having diastereomers
 represented by S.sub.xa --R.sub.4z and S.sub.xb --R.sub.4q.
 In another embodiment, the diastereomers of each of the compounds
 represented by formulae (Ia) and (Ib) in the composition are S.sub.xa
 --R.sub.4q and S.sub.xa --R.sub.4z, or one or more pharmaceutically
 acceptable salts, solvates, hydrates, or combinations thereof of the
 compound represented by formula (Ia). In one example of this embodiment,
 the above composition is essentially free of compounds represented by
 formulae (Ia) and (Ib) having diastereomers represented by S.sub.xb
 --R.sub.4q and/or S.sub.xb --R.sub.4z. Typically, this composition is in
 the form of an oil which, using the technique taught hereinafter, may form
 a crystalline, preferably a microcrystalline composition. Otherwise, a
 "salt" of such composition may also be formed independently or,
 preferably, in situ, as described hereinafter.
 In another embodiment, the diastereomers of the compounds represented by
 formulae (Ia) and (Ib) which are present in the above compositions may
 include the following: (a) S.sub.xb --R.sub.4q and (b) S.sub.xa
 --R.sub.4z., or one or more pharmaceutically acceptable salts, solvates,
 hydrates, or combinations thereof of the compounds represented by formulae
 (Ia) and (Ib). In one example of this embodiment, the enantiomer
 represented by S.sub.xa in each compound in each composition is present in
 optically pure form as defined herein. In another example of this
 embodiment, the composition is essentially free from compounds having
 diastereomers represented by S.sub.xa --R.sub.4q and S.sub.xb --R.sub.4z.
 The above compositions comprising the various diastereomer components may
 be present in various amounts. In another example of the above
 embodiments, the percentage of enantiomers represented by R.sub.4z for
 either or both of the compounds represented by formulae (Ia) and (Ib)
 comprises greater than about 5 percent (w/w) and less than about 49
 percent (w/w) in the compounds represented by formulae (Ia) and (Ib) such
 that the sum of the total percentage of such enantiomers represented by
 R.sub.4q and R.sub.4z equals about 100 percent (w/w). In another example
 of the above embodiments, the percentage of enantiomers represented by
 R.sub.4z for either or both of the compounds represented by formulae (Ia)
 and (Ib) comprises greater than about 51 percent (w/w) in the compounds
 represented by formulae (Ia) and (Ib) such that the sum of the total
 percentage of such enantiomers represented by R.sub.4q and R.sub.4z equals
 about 100 percent (w/w).
 In another embodiment, the diastereomers of the compounds represented by
 formulae (Ia) and (Ib) which are present in the above compositions may
 include the following: (a) S.sub.xb --R.sub.4q and (b) S.sub.xb
 --R.sub.4z., or one or more pharmaceutically acceptable salts, solvates,
 hydrates, or combinations thereof of the compounds represented by formulae
 (Ia) and (Ib). In one example of this embodiment, the enantiomer
 represented by S.sub.xa in each compound in each composition is present in
 optically pure form as defined herein. In another example of this
 embodiment, the composition is essentially free from compounds having
 diastereomers represented by S.sub.xa --R.sub.4q and S.sub.xa --R.sub.4z.
 The above compositions comprising the various diastereomer components may
 be present in various amounts. In another example of the above
 embodiments, the percentage of enantiomers represented by R.sub.4z for
 either or both of the compounds represented by formulae (Ia) and (Ib)
 comprises greater than about 5 percent (w/w) and less than about 49
 percent (w/w) in the compounds represented by formulae (Ia) and (Ib) such
 that the sum of the total percentage of such enantiomers represented by
 R.sub.4q and R.sub.4z equals about 100 percent (w/w). In another example
 of the above embodiments, the percentage of enantiomers represented by
 R.sub.4z for either or both of the compounds represented by formulae (Ia)
 and (Ib) comprises greater than about 51 percent (w/w) in the compounds
 represented by formulae (Ia) and (Ib) such that the sum of the total
 percentage of such enantiomers represented by R.sub.4q and R.sub.4z equals
 about 100 percent (w/w).
 In another embodiment of the above composition, the diastereomers of each
 of such compounds represented by formulae (Ia) and (Ib) each is S.sub.xa
 --R.sub.4q, or one or more pharmaceutically acceptable salts, solvates,
 hydrates, or combinations thereof of the compounds represented by formulae
 (Ia) and (Ib). In various embodiments of the compositions of the
 invention, the compounds represented by formulae (Ia) and (Ib) may be
 present in optically pure form, with the term optically pure being
 preferably defined hereinabove. In another example of this embodiment, the
 composition comprising compounds represented by formulae (Ia) and (Ib) are
 essentially free of such compounds comprising each of the diastereomers
 represented by: (a) S.sub.xa --R.sub.4z ; (b) S.sub.xb --R.sub.4q ; and
 (c) S.sub.xb --R.sub.4z.
 In another embodiment of the above composition, the diastereomers of each
 of such compounds represented by formulae (Ia) and (Ib) each is S.sub.xa
 --R.sub.4z, or one or more pharmaceutically acceptable salts, solvates,
 hydrates, or combinations thereof of the compounds represented by formulae
 (Ia) and (Ib). In various embodiments of the compositions of the
 invention, the compounds represented by formulae (Ia) and (Ib) may be
 present in optically pure form, with the term optically pure being
 preferably defined herein. In another example of this embodiment, the
 composition comprising compounds represented by formulae (Ia) and (Ib) are
 essentially free of such compounds comprising each of the diastereomers
 represented by: (a) S.sub.xa --R.sub.4q (b) S.sub.xb --R.sub.4q and (c)
 S.sub.xb --R.sub.4z.
 In another embodiment of the above composition, the diastereomers of each
 of such compounds represented by formulae (Ia) and (Ib) each is S.sub.xb
 --R.sub.4q, or one or more pharmaceutically acceptable salts, solvates,
 hydrates, or combinations thereof of the compounds represented by formulae
 (Ia) and (Ib). In various embodiments of the compositions of the
 invention, the compounds represented by formulae (Ia) and (Ib) may be
 present in optically pure form, with the term optically pure being
 preferably defined herein. In another example of this embodiment, the
 composition comprising compounds represented by formulae (Ia) and (Ib) are
 essentially free of such compounds comprising each of the diastereomers
 represented by: (a) S.sub.xa --R.sub.4q (b) S.sub.xa --R.sub.4z and (c)
 S.sub.xb --R.sub.4z.
 In another embodiment of the above composition, the diastereomers of each
 of such compounds represented by formulae (Ia) and (Ib) each is S.sub.xb
 --R.sub.4z, or one or more pharmaceutically acceptable salts, solvates,
 hydrates, or combinations thereof of the compounds represented by formulae
 (Ia) and (Ib). In various embodiments of the compositions of the
 invention, the compounds represented by formulae (Ia) and (Ib) may be
 present in optically pure form, with the term optically pure being
 preferably defined herein. In another example of this embodiment, the
 composition comprising compounds represented by formulae (Ia) and (Ib) are
 essentially free of such compounds comprising each of the diastereomers
 represented by: (a) S.sub.xa --R.sub.4q (b) S.sub.xa --R.sub.4z and (c)
 S.sub.xb --R.sub.4q.
 Any of the composition embodiments may include, for example, compounds of
 the pairs Iai-Ibi, Iaii-Ibii, Iaiii-Ibiii, and Iaiv-Ibiv as follows:
 ##STR18##
 wherein each S.sub.x is S.sub.xa ;
 or one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof the composition;
 ##STR19##
 wherein each S.sub.x is S.sub.xa ;
 or one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof the composition;
 ##STR20##
 wherein each S.sub.x is S.sub.xb ;
 or one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof the composition;
 ##STR21##
 wherein each S.sub.x is S.sub.xb ;
 or one or more pharmaceutically acceptable salts, solvates, hydrates, or
 combinations thereof the composition.
 Any of the above composition embodiments comprising any of the compounds
 represented by formulae (Ia) and (Ib), individual species of compounds
 (Iai)-(Ibi), (Iaii)-(Ibii), (Iaiii)-(Ibiii), and (Iaiv)-(Ibiv),
 diastereromers thereof, or any pharmaceutically acceptable salts,
 solvates, hydrates, or combinations thereof, may be present in crystalline
 form.
 The invention also provides compositions of active pharmaceutical
 ingredient ("API") comprising any of the above composition embodiments.
 Advantageously, any of the compositions comprising compounds represented
 by formulae (Ia) and (Ib) may also comprise any of the specific
 compositions represented by formulae (Iai)-(Ibi); (Iaii)-(Ibii);
 (Iaiii)-(Ibiii); and (Iaiv)-(Ibiv) or one or more pharmaceutically
 acceptable salts, solvates, hydrates, polymorphs, or combinations thereof,
 whether in crystalline form, amorphous form, or a combination thereof, can
 be used in any such API compositions.
 The compounds represented by formulae (Ia) and (Ib) may be prepared as
 described in various embodiments. More specifically, the methods describe
 forming the compounds in solution. The presence of either the compound of
 formula (Ia) or (Ia)/(Ib) in solution causes formation of the
 corresponding tautomer. Thus, these methods essentially describe forming
 each series of compounds. However, the present invention provides novel
 compounds of the formulae (Ia) and (Ib) in their respective solid states.
 Compounds of the present invention are prepared by using a variety of
 synthetic processes. For example, in the crystallization of "omeprazole"
 from solution, the amount of compound represented by formula (Ia)
 significantly varies by the rate of crystallization. Accordingly, slight
 variations within the same process as taught in the prior art, such
 process not being appropriately controlled or defined as to regulate the
 amount of previously unknown compound represented by formula (Ia), will
 result in various ratios of compounds represented by formula (Ia) to
 compounds represented by formula (Ib).
 Additionally, when using such process represented in the prior art,
 negligible or trace amounts of previously unknown compounds are formed as
 described herein. For example, in the preparation of "omeprazole" as
 referenced in the immediately preceding paragraph, compounds having the
 previously unknown diastereomers S.sub.xa --R.sub.4q and S.sub.xb
 --R.sub.4z are formed with varying and inconsistent ratios of compounds
 represented by formulae (Ia) and (Ib). Also formed in trace quantities,
 and typically in amorphous form, are compounds represented by formulae
 (Ia) and (Ib) having the previously unknown diastereomers S.sub.xa
 --R.sub.4z and S.sub.xb --R.sub.4q.
 Furthermore, when prior art processes are used with the intent of forming
 "salts" of "omeprazole", the rather broad teachings may result in salts,
 but may also result in the formation of novel complexes which are
 described herein.
 Accordingly, the processes taught in the prior art for the preparation of
 "omeprazole" as well as "esomeprazole" (the intended S-isomer of
 "omeprazole") provide quantities of previously unknown and unrecognized
 compounds having pharmaceutical activity, or which are used as
 intermediates in the preparation of pharmaceutically active compounds of
 the present invention. Furthermore, many such processes do not invariably
 provide the same result when conducted as taught in the prior art.
 Embodiments describing methods of preparing the compounds of the present
 invention follow. In various embodiments, neither R.sub.3 nor R.sub.5 are
 not hydrogen when R.sub.4 is alkoxy.
 In one embodiment, the compounds may be formed by oxidizing a compound of
 formula (II):
 ##STR22##
 wherein R is alkoxy at the 5- or 6-position, R.sub.1, R.sub.2, R.sub.3,
 R.sub.4, and R.sub.5 have the meanings defined above, to form the compound
 of formulas (Ia) or (Ib). The oxidation of the sulfur atom to sulfinyl
 (S.fwdarw.O) typically takes place in the presence of an oxidizing agent
 selected from the group consisting of nitric acid, hydrogen peroxide,
 peracids, peresters, ozone, dinitrogentetraoxide, iodosobenzene,
 N-halosuccinimide, 1 -chlorobenzotriazole, t-butylhypochlorite,
 diazobicyclo-[2,2,2,]-octane bromine complex, sodium metaperiodate,
 selenium dioxide, manganese dioxide, chromic acid, cericammonium nitrate,
 bromine, chlorine, and sulfuryl chloride. The oxidation usually takes
 place in a solvent wherein the oxidizing agent is present in some excess
 in relation to the product to be oxidized.
 In another embodiment, a compound of the formula (III):
 ##STR23##
 wherein R, R.sub.1, and R.sub.2 are defined herein, and M is a metal
 selected from potassium, sodium, and lithium; may be reacted with a
 compound of the formula (IV):
 ##STR24##
 wherein R.sub.3, R.sub.4, and R.sub.5 have the same meanings as given
 above, and Z is a reactive esterified hydroxy group to form compounds of
 formulas (Ia) and (Ib).
 In another embodiment, a compound of formula (V):
 ##STR25##
 wherein R and R.sub.1 are defined herein and Z.sub.1 is SH or a reactive
 esterified hydroxy group, is reacted with a compound of the formula (VI):
 ##STR26##
 wherein R.sub.2, R.sub.3, R.sub.4, and R.sub.5 have the same meanings as
 given above, and Z.sub.2 is a reactive esterified hydroxy group or SH, to
 form an intermediate of formula (II) above, which then is oxidized to give
 compounds of formulas (Ia) and (Ib).
 In another embodiment, a compound of formula (VII):
 ##STR27##
 wherein R and R.sub.1 are defined above is reacted with a compound of the
 formula (VII):
 ##STR28##
 wherein R.sub.1, R.sub.3, R.sub.4, and R.sub.5 are defined above, to form
 an intermediate of formula (II) above, which then is oxidized to give
 compounds of formulas (Ia) and (Ib).
 In the reactions above, Z, Z.sub.1, and Z.sub.2 may be a reactive
 esterified hydroxy group which is a hydroxy group esterified with strong,
 inorganic or organic acid, preferably a hydrohalogen acid, such as
 hydrochloric acid, hydrobromic acid, or hydroiodic acid, as well as
 sulfuric acid or a strong organic sulfonic acid, such as, for example, a
 strong aromatic acid, e.g., benzenesulfonic acid, 4-bromobenzenesulfonic
 acid or 4-toluenesulfonic acid. The starting materials are known or may,
 if they should be new, be obtained according to processes known per se.
 In another embodiment, compounds of formulas (Ia) and (Ib) may be formed by
 reacting a compound of the formula (II):
 ##STR29##
 wherein R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 have the
 meanings defined above, with m-chloroperoxybenzoic acid in a methylene
 chloride solution. The reaction should be carried out at a substantially
 constant pH. The reaction product is then extracted with a base (e.g.,
 NaOH) and the aqueous phase is separated from the organic phase. An alkyl
 formate is added to the aqueous phase resulting in the crystallization of
 the compounds of formulas (Ia) and (Ib).
 The invention also provides methods for producing compositions of compounds
 represented by formula (Ia) and (Ib). As discussed herein, Applicants have
 unexpectedly discovered that it is possible to obtain the compounds of
 formulae (Ia) and (Ib) in co-crystallized compositions in various amounts
 relative to one another according to techniques taught below.
 Applicants have confirmed that solution NMR reveals the tautomerization of
 the compounds of formulas (Ia) and (Ib). Solution NMR suggests that the
 tautomerization reaches an equilibrium at approximately a 2:1 ratio of
 compounds represented by formula (Ia) to compounds represented by formula
 (Ib). Upon crystallization and isolation, the compound of formula (Ia)
 appears to be the more energetically favorable isomer and crystallizes
 first. This equilibration/crystallization process allows for the
 predominant isolation of the solid (e.g., crystalline) isomer of compound
 of formula (Ia). Through solution NMR experiments, it is believed that the
 exchange rate of the amine proton during tautomerization may be pH
 dependent. For example, with the addition of a small amount of base, the
 proton exchange rate was shown to slow, and two distinct proton NMR peaks
 were observed for each of the benzimidazole aromatic protons.
 Methods for forming compositions comprising compounds of formulae (Ia) and
 (Ib) are described herein with reference to certain embodiments. However,
 variations from these embodiments may be carried out without departing
 from these separation methods described by the present invention.
 As alluded to above, Applicants have determined that compositions of
 compounds of formulae (Ia) and/or (Ib) may be formed in relative ratios of
 the compounds to one another not suggested by the prior art. In one
 embodiment, the method may provide this compound substantially free from
 its corresponding isomer (the compound of formula (Ib)). Preferably, the
 compound represented by formula (Ia) is present in an amount ranging from
 about 96 to about 99 percent (w/w). The method generally includes first
 providing a solution comprising the tautomers of formulas (Ia) and (Ib)
 and a solvent. Examples of solvents include, but are not limited to, an
 aqueous solvent (e.g., water) or an organic solvent. Examples of organic
 solvents include, but are not limited to, a ketone (e.g., acetone), a
 nitrile solvent (e.g., acetonitrile, acetonitrile/water), an amine solvent
 (e.g., dimethyl formamide (DMF) or pyridine), an aryl solvent (e.g.,
 toluene), a halogenated solvent (e.g., methylene chloride, chloroform), an
 alcohol (e.g., methanol, ethanol), ammonium hydroxide, and a
 sulfur-containing solvent (e.g., dimethyl sulfoxide (DMSO)). Mixtures of
 the above may also be employed.
 Preferably, the solution is saturated. The solution is evaporated slowly
 (preferably from about 3 days to about 7 days) until crystal formation is
 achieved, with the compounds represented by formulae (Ia) and/or (Ib)
 co-crystallizing in the same lattice.
 Advantageously, the relative amounts of compounds of formulae (Ia) and (Ib)
 that may be obtained in co-crystalline form can be manipulated by
 judicious selection of a number of variables relating, but not necessarily
 limited to, solvent choice, temperature, and vapor diffusion control rate.
 The selection of solvent for use in the method may be governed by various
 considerations. For example, although not intending to be bound by theory,
 it is believed that the use of slower evaporation solvents (e.g., DMF) and
 their controlled evaporation at lower temperatures produces crystals with
 a higher percentage of the compound represented by formula (Ia) in the
 crystalline lattice, preferably compound of formula (Ia) being pure or
 essentially pure as defined herein. In other embodiments, solvents with
 lower vapor pressures (e.g., methylene chloride, ethanol, and chloroform)
 are capable of yielding crystals with higher percentages of compound
 represented by formula (Ib) in the crystalline lattice, typically up to
 about 20 percent (w/w) to about 30 percent (w/w) of the compound
 represented by formula (Ib).
 With all other factors being consistent, temperature does not appear to
 significantly influence which of the compounds of the present invention
 (e.g. compounds represented by formulae (Ia) and (Ib)) will be formed, but
 may influence the size and clarity of such crystals. Typically,
 temperatures below ambient temperature provides crystals having larger
 size and better clarity.
 The crystallization (e.g., recrystallization) rate may also be influenced
 by the rate of solvent evaporation, and is influenced by using methods
 well known in the art. In one embodiment, by exposing a sample of
 compounds represented by formulae (Ia) and (Ib) to the surrounding
 environment, the rate of evaporation should increase and the formation of
 the compound represented by formula (Ib) in the crystal lattice should
 increase. Conversely, in another embodiment, by controlling (i.e.,
 slowing) the rate of evaporation, the recrystallization process should be
 slowed, thus yielding purer amounts of the compound represented by formula
 (Ia).
 Accordingly, one may manipulate various processing variables as set forth
 herein to yield the percentage of compound(s) represented by formulae (Ia)
 and/or (Ib) as desired. For example, in one preferred embodiment, using
 DMF, reduced evaporation, and lowered temperatures, higher percentages of
 the compound represented by formula (Ia) are obtained, preferably from
 about 96 to about 100 percent (w/w). Crystals containing the highest
 percentages of the compound represented by formula (Ib) (e.g., from about
 10 percent to about 40 percent (w/w), and more preferably about 10 percent
 to about 20 percent) may be produced using a solvent comprising ethanol
 and ammonium hydroxide, reduced evaporation, and ambient temperature.
 The structure of the compound of formula (Ia), and in particular,
 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz
 imidazole, has been confirmed by x-ray single crystal analyses on isolated
 crystals formed in accordance with the above method.
 By employing the above method of obtaining the compound represented by
 formula (Ia) in solid state, one obtains the (-) and (+) enantiomers as a
 racemic mixture, with these enantiomers including various amounts of
 diastereomers as set forth herein. In one embodiment, Applicants have
 discovered that the (-) and (+) enantiomers may be predominantly present
 as the S--S and R--R diastereomers respectively. Although not intending to
 be bound by theory, in this embodiment, the two molecules (i.e., compounds
 of formulae (Ia) and (Ib)) co-crystallize in a centric space group in
 which the molecules are related to each other through a center of
 inversion and linked by hydrogen bonding from the amine hydrogens to the
 sulfoxide oxygens. The methoxy methyl is directed towards the center of
 the bridged complex. Examination of the contact distances in the region
 where the other methoxy methyl would presumably reside demonstrates that
 there is not adequate space within the lattice for the other diastereomers
 (S--R and R--S) to co-exist. In this embodiment, the compound represented
 by formula (Ia) may comprise about 99 percent (w/w) of the R--R and S--S
 diastereomers and the remaining percentage of other components which may
 include, for example, the diastereomers S--R and R--S, generally in
 amorphous form.
 In the above embodiment, the crystallization of the compounds represented
 by formulae (Ia) and (Ib) is believed to be controlled thermodynamically
 by a bipyrimidal inversion equilibrium at the sulfoxide chiral center
 which forces the R--S diastereomer to S--S and the S--R diastereomer to
 R--R diastereomer. Such behavior may be confirmed by examining the x-ray
 crystal structure and more specifically, the crystal packing. Not
 intending to be bound by theory, it is believed that the molecular packing
 does not provide adequate area for the other diastereomers to be present
 within the current crystal lattice.
 Upon obtaining a composition comprising the compound of formula (Ia) as
 described above, one may apply a suitable technique to resolve the
 individual (-) and (+) enantiomers. One may then apply a suitable
 technique (including, for example, those described subsequently) to
 resolve the diastereomer components in the (-) and (+) enantiomers. With
 respect to the (-) enantiomer of the compound represented by formula (Ia),
 in a number of embodiments, the above techniques are capable of yielding
 about 95 percent (w/w) of the S--S diastereomer and about 5 percent (w/w)
 of the S--R diastereomer of the compound of formula (Ia), particularly in
 the specific embodiment in which compound (Ia) is described by compounds
 of the formulae (Iai) and (Iaii). Although not intending to be bound by
 theory, it is believed that the bipyramidal inversion equilibrium at the
 sulfoxide chiral center forces the R--S diastereomer to the S--S
 diastereomer of the compound represented by formula (Ia). Moreover, the
 composition of the resolved (+) enantiomer by the resolution techniques
 set forth herein allow for the formation of predominantly the R--R
 diastereomer (e.g., about 95 percent (w/w)). Similar to the formation of
 the S--S diastereomer, a bipyramidal inversion equilibrium is believed to
 occur forcing the S--R diastereomer to the R--R diastereomer.
 Alternatively, in another embodiment, a biosynthesis resolution method
 allows for the (-) enantiomer to be resolved from the (+) enantiomer
 wherein the composition of the (-) enantiomer includes about 50 percent
 (w/w) of the S--S diastereomer and about 50 percent (w/w) of the S--R
 diastereomer. Likewise, the (+) diastereomer resolved by this biosynthesis
 method includes about 50 percent (w/w) of the R--S diastereomer and about
 50percent (w/w) of the R--R diastereomer.
 The above techniques can also be used to co-crystallize a metal ion
 analogue of the compounds represented by formulae (Ia) and (Ib) in the
 amounts set forth above. Redissolving such compound(s) is believed to
 initiate the bipyramidal inversion which generates the distereomer
 components S--S, S--R, R--S, and R--R in amounts which are believed to
 depend upon, but not potentially limited to, the bipyridimal inversion
 equilibrium rate, the time it takes to create the metal analog, and the
 time it takes to crystallize the analog. It should be appreciated that
 these variables may be manipulated by one skilled in the art. Preferably,
 the range of each of the four diastereomers can range from about a 60:40
 ratio to about a 100:0 ratio of enantiomeric S--R and R--S analogs
 compound to S--S and R--R analogs.
 The present invention also provides a method of forming a compound of
 formula (Ib) in the solid state. In a preferred specific embodiment, the
 method encompasses increasing the level of the compound represented by
 formula (Ib) in a composition comprising the compounds represented by
 formulae (Ia) and (Ib). The method comprises subjecting a compound of
 formula (Ia) to grinding conditions sufficient to permit a solid state
 phase transformation of the compound of formula (Ia) to a compound of
 formula (Ib). Preferably, the compound represented by the formula (Ia) is
 present in a composition and the above method increases the percentage of
 the compound represented by formula (Ib) present in the composition. In
 this embodiment, prior to the subjecting step, the composition may contain
 the compound represented by formula (Ia) essentially free from the
 compound represented by formula (Ib), although it should be appreciated
 that other examples are contemplated in which the composition comprises
 the compounds of formulae (Ia) and (Ib) in amounts set forth herein.
 Various conditions may be manipulated during the subjecting step to govern
 the amount of compound represented by formula (Ib), e.g., revolutions per
 minute (RPM) and length of subjecting step. The subjecting step is
 preferably carried out from about 350 rpm to about 500 rpm, more
 preferably from about 350 rpm to about 450 rpm, and most preferably about
 450 rpm. A preferred time for carrying out the subjecting step is from
 about 5 to about 30 minutes, more preferably from about 10 min to about 30
 min, and most preferably about 15 minutes Advantageously, the compounds
 are not degraded during this operation. The subjecting step may be carried
 out by various machines that apply appropriate grinding energies to solid
 materials. Preferably, the machine is a mechanical grinder. One example of
 a suitable grinder is set forth in U.S. Pat. No. 5,773,173 to Whittle et
 al., the disclosure of which is incorporated herein by reference in its
 entirety. It should be appreciated that one may employ embodiments other
 than those described above and still be within the scope of the method of
 forming the compound of the formula (Ib) in solid state.
 Although not intending to be bound by theory, the compound of formula (Ia)
 is believed to be crystalline with little amorphous content. However, when
 grinding is applied to a solid sample comprising the compound of formulas
 (Ia), and in a preferred embodiment the compounds of formulae (Ia) and
 (Ib), an increase in the amorphous character of the sample is believed to
 result along with an increase in the amount of compound of formula (Ib).
 Again not intending to be bound by theory, it is believed that the sample
 undergoes a solid state transformation and "recrystallizes" or transforms
 over a relatively short period of time from the more amorphous state to a
 more crystalline state subsequent to grinding. Nonetheless, it is believed
 that by performing multiple grinding steps in sequence, (i.e., grinding
 followed by relaxation followed by grinding) one may obtain a solid sample
 that becomes more amorphous in character and hence comprises a greater
 amount of the compound of the formula (Ib) as opposed to a sample that has
 experienced a lower amount of grinding.
 The above method may provide various amounts of the compound of formula
 (Ib).
 The structure of the compound of formula (Ib) can be confirmed by solid
 state techniques such as, for example, X-ray powder diffraction patterns,
 Raman, FTIR, solid state NMR, and thermal analysis, of the ground material
 and the unground material. For example, comparison of the two powder
 patterns showed distinct decreases in intensity, broadening of the peaks,
 and an increase in the amorphous nature for the ground material. The
 ground material showed a powder pattern that is more consistent with the
 proposed more amorphous nature of the compound of formula (Ib), e.g.,
 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz
 imidazole.
 The present invention also provides the compounds of formulae (Ia) and (Ib)
 in the form of pharmaceutically acceptable salts as described hereinbelow.
 Similar to the making of the compounds of formulae (Ia) and/or (Ib)
 described above, the making of a salt of each of the compounds of formulae
 (Ia) and/or (Ib) in solution results in the making of salts of both
 compounds due to tautomerization occurring in solution. Thus, these
 methods describe making salts of both compounds.
 Depending on the process conditions and the starting materials, the end
 product of the synthetic processes for preparing compounds represented by
 formulae (Ia) and/or (Ib) is typically obtained as a free base. Basic,
 neutral or mixed salts may be obtained as well as solvates and hemi-,
 mono-, sesqui- or polyhydrates. Examples of suitable bases for salt
 formation include, but is not limited to, compounds containing alkali
 metals or alkali earth metals, although it is appreciated by the skilled
 artisan that bases containing other types of metals may be used. Examples
 of inorganic bases include, but are not limited to, sodium hydroxide,
 sodium carbonate, sodium bicarbonate, potassium hydroxide, calcium
 hydroxide, magnesium hydroxide, and the like. Organic bases in the form
 of, for example, nitrogen-containing components may be also used.
 Exemplary nitrogen-containing compounds include, but are not limited to,
 ammonium, organic amines, and the like. The free bases that are obtained
 may form salts with organic or inorganic acids.
 As discussed in greater detail herein, metal hydrides, particularly sodium
 hydride, are preferably used in making the salts of the compounds of the
 present invention. Other methods that have been conventionally thought to
 be useful in making salts of such compounds have been found by Applicants
 to not invariably result in the formation of such salts, but instead have
 resulted in complex formation. Thus, the method of making such salts
 employing the metal hydrides of these compounds is not suggested by the
 prior art.
 Acid addition salts may be difficult to form because of the acid labile
 nature of the compounds of the invention, but could be formed at a pH
 above 6.0 since the stability of the compounds increases. Acids suitable
 for making such salts may include, but are not limited to, hydrohalogen
 acids, sulfonic, phosphoric, nitric, and perchloric acids; aliphatic,
 alicyclic, aromatic, heterocyclic carboxy or sulfonic acids, such as
 formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric,
 citric, ascorbic, maleic, hydroxymaleic, pyruvic, phenylacetic, benzoic,
 p-aminobenzoic, antranilic, p-hydroxybenzoic, salicylic or
 p-aminosalicylic acid, embonic, methanesulfonic, ethanesulfonic,
 hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic,
 toluenesulfonic, naphtylsulfonic or sulfanilic acids; methionine,
 tryptophane, lysine or arginine.
 These or other salts of the new compounds, as e.g., picrates, may serve as
 purifying agents of the free bases obtained. Salts of the bases may be
 formed, separated from solution, and then the free base may be recovered
 from a new salt solution in a purer state. Because of the relationship
 between the new compounds in free base form and their salts, it will be
 understood that the corresponding salts are included within the scope of
 the invention.
 The salts may be prepared by various techniques. For example, such salts
 can be prepared from organic compounds when that compound has an "acidic"
 proton. The proton may be removed, for example, by a type of base that
 allows for the formation of an anionic species of the compound countered
 by the cation. In embodiments encompassing polar, protic environments,
 such as an alkali or alkaline metal hydroxide or alkaline metal alkoxide
 present in an alcohol or mixed organic solvent such as a
 2-butanone/toluene mixture it is believed that the conversion to the salt
 may be governed by pKa differences. In various embodiments, such
 techniques are capable of yielding salts of the compounds of the present
 invention having the diastereomers represented by S.sub.xa --R.sub.4z and
 S.sub.xb --R.sub.4q in a range from about 60 to about 70 percent (w/w).
 Another example of a method for preparing salts of compounds represented by
 formulae (Ia) and/or (Ib) comprises subjecting such compounds to a polar,
 aprotic environment to form such salts. Examples of polar, aprotic
 environments include, for example, an alkali or alkaline metal hydride in
 an organic solvent (e.g., tetrahydrofuran (THF) or dimethylformamide (DMF)
 Although not intending to be bound by theory, in polar, aprotic
 environments, the salt conversion may be governed by factors such as
 solubility of both the organic compound and the base used and the steric
 hindrance interactions. Although both types of reactions (e.g., polar,
 protic environments and polar, aprotic environments) can be use in forming
 the salts, reactions taking place in polar, aprotic environments are
 preferred. For example, using a polar, aprotic environment may preferably
 provide from about 90 to about 95 percent (w/w) yield of salts of the
 compounds, and/or compositions of the present invention. Although various
 alkali and alkaline metal salts can be made using the above methods, it is
 preferred to form sodium or magnesium salts of compounds of the present
 invention.
 The salts may be formed by various reactions. For example, in one
 embodiment, a complex may be formed by reacting the compounds represented
 by formulae (Ia) with a cation A.sup.z+ by a suitable technique, e.g.,
 ion-pair extraction. In the above embodiment, A is lithium, sodium,
 potassium, magnesium, calcium, titanium(4+), N.sup.+ (R.sup.1).sub.4, or:
 ##STR30##
 wherein R.sup.1 is an alkyl group containing 1 to 4 carbon atoms, and z is
 1, 2, or 4. For example, tetrabutylammonium salts of the invention may be
 prepared by dissolving the A.sup.z+ salt in water containing one or more
 tetrabutylammonium compounds such as, for example, the chloride or
 hydroxide followed by extraction of the tetrabutylammonium salt into a
 methylene chloride phase, and subsequent isolation of the
 tetrabutylammonium salt. In this manner, other tetraalkylammonium salts
 may be prepared.
 In one embodiment, the salt of the compound of formula (I') may be formed
 by reacting the compound of formulae (Ia) and/or (Ib) with a base capable
 of releasing the cation A.sup.z+ wherein z is 1, 2, or 4; and A is
 lithium, sodium, potassium, magnesium, calcium, titanium(4+), N.sup.+
 (R.sup.1).sub.4, or:
 ##STR31##
 wherein R.sup.1 is an alkyl group containing 1 to 4 carbon atoms, to
 provide a salt of the formula (I'):
 ##STR32##
 wherein R is alkoxy in the 5- or 6-position: R.sub.1 is selected from the
 group consisting of hydrogen, alkyl, halogen, carboalkoxy, alkoxy, and
 alkanoyl; R.sub.2 is hydrogen or alkyl; and R.sub.3, R.sub.4, and R.sub.5
 may be the same or different and are each selected from the group
 consisting of hydrogen, alkyl, alkoxy, and alkoxyalkoxy, and wherein z and
 A.sup.z+ are defined above.
 In one example, lithium, potassium, or sodium salts of the formula (I') may
 be prepared by treating the compounds of the formulae (Ia) and/or (Ib)
 with LiOH, NaOH, or KOH in an aqueous or nonaqueous medium, or with
 LiOR.sup.1, LiNH.sub.2, LiNR.sup.1.sub.2, NaOR.sup.1, NaNH.sub.2,
 NaNR.sup.1.sub.2, KOR.sup.1, KNH.sub.2, KNR.sup.1.sub.2 wherein R.sup.1 is
 defined above, in an aqueous or a nonaqueous medium. Magnesium, calcium,
 or titanium salts may be prepared by treating a compound of the formulas
 (Ia) or (Ib) with Mg(OR.sup.1).sub.2, Ca(OR.sup.1).sub.2, CaH.sub.2,
 Ti(OR.sup.1).sub.4 or TiH.sub.4 , wherein R.sup.1 is defined herein, in a
 nonaqueous solvent such as an alcohol (for the alcoholates), e.g., ROH, or
 in an ether such as tetrahydrofuran.
 In another example, a salt of the compound of formula (I') wherein A is:
 ##STR33##
 may be prepared by treating compounds of the present invention with a
 strong base of the formula:
 ##STR34##
 dissolved in a solvent such as, for example, an alcohol.
 A salt represented by formula (I') may be converted to another salt of the
 same formula by exchanging the cation. When both the starting material and
 the salt obtained as final product are sufficiently soluble, such an
 exchange may be performed by using a cation-exchange resin saturated with
 the cation desired in the product. The exchange may also be performed by
 utilizing the low solubility of a desired salt.
 The reaction between the compound of formulas (Ia) and/or (Ib) and A.sup.z+
 may also be carried out by ion-pair extraction. For example,
 tetrabutylammonium salts of the invention may be prepared by dissolving
 the Na+salt in water containing one or more tetrabutylammonium compounds
 followed by extraction of the tetrabutylammonium salt into a methylene
 chloride phase, and subsequent isolation of the tetrabutylammonium salt.
 In this manner, other tetraalkylammonium salts may be prepared.
 Illustrative examples of the radical R.sup.1 are methyl, ethyl, n-propyl,
 n-butyl, isobutyl, sec-butyl, and tert-butyl.
 A preferred method for forming magnesium salts of compounds of the present
 invention is characterized by the following consecutive steps: a) treating
 at least one compound of formulae (Ia) and/or (Ib) or salts thereof with
 magnesium alcoholate in a solution; b) separating inorganic salts from the
 reaction mixture; c) crystallizing the magnesium salts of such formulae
 (Ia) and/or (Ib); d) isolating the obtained crystalline magnesium salts
 and, optionally, e) purifying and drying the crystalline magnesium salts
 using conventional methods.
 A process for manufacturing the magnesium salts is described as follows: a
 lower alcohol, such as methanol, ethanol, n-propanol or iso-propanol,
 preferably methanol, is treated in a solution of polar solvents with a
 weighed amount of magnesium at temperatures between about 0.degree. C. and
 reflux temperature. The temperature should preferably be between about
 10.degree. C. and about 40.degree. C. After addition of the magnesium to
 the solution the temperature can, in a second step be raised further to
 between about 0.degree. C. and reflux temperature, preferably about
 20.degree. C. to about 50.degree. C. After termination of the reaction the
 temperature is reduced to about 0.degree. C. to about 40.degree. C.,
 preferably about 10.degree. C. to about 25.degree. C. The compound of
 formula (Ia) or (Ib) or a salt thereof is then added to the solution and
 after termination of the reaction the mixture is cooled to about
 -10.degree. C. to about +20.degree. C, preferably about -5.degree. C. to
 about +5.degree. C. The solvent is then evaporated to about 40 to about 60
 percent of the initial volume, which makes the inorganic salts
 precipitate. The precipitate is separated from the reaction solution for
 example by centrifugation or filtration and the solution is heated from
 about 5.degree. C. to about 30.degree. C. whereafter the solution is
 seeded with magnesium crystals of the compound of formula (Ia) or (Ib). An
 amount of water, which is approximately equal to the volume of the
 solution, is added to start the crystallization. The solution is cooled to
 about -10.degree. C. to about +20.degree. C., preferably about 0.degree.
 C. to about 10.degree. C. to complete the crystallization. The crystals
 are then separated from the mother liquid for example by centrifugation or
 filtration and washed with polar solvents preferably an aqueous lower
 alcohol such as aqueous methanol. Finally, the produced crystals are dried
 preferably under reduced pressure and heating.
 The magnesium salts may include various amounts of the compounds of the
 formulae (Ia) and/or (Ib). For example, in one embodiment, a magnesium
 salt composition may preferably comprise up to about 30 percent (w/w) of
 the compound of formula (Ib), and more preferably about 27 percent (w/w)
 of the compound of formula (Ib).
 In another aspect, the invention also provides complexes of the compound
 represented by the formulae (Ia) and/or (Ib). In particular, the invention
 provides a composition comprising a complex of: (a) two or more compounds
 encompassed by compositions set forth herein comprising compounds
 represented by formulae (Ia) and/or (Ib); at least one atom of a metal
 cation, preferably an alkali or alkaline metal cation. Exemplary metal
 cations are selected from the Groups IA, IIA, and IIIa of the periodic
 table although other cations may be employed. Preferably, the composition
 is present in crystalline form. Sodium and magnesium each are examples of
 preferred cations.
 Such compositions of the present invention may employ solvent(s) that are
 typically employed in forming complexes. In a preferred embodiment, such
 compositions further include two solvents. The solvents are those which
 are capable of donating a pair of electrons, alcohols, THF, DMF, DMSO, and
 mixtures thereof. The complexes of the invention may be formed by using
 materials which are known to be used in forming complexes, e.g., alkoxides
 and hydroxides of metal cations such as, without limitation, those
 described above. The two or more compounds represented by formula (Ia) may
 be the same or different and may be present as compounds with any one of
 the four diastereomer configurations (e.g., S.sub.xa --R.sub.4q, S.sub.xa
 --R.sub.4z, S.sub.xb --R.sub.4q, and S.sub.xb --R.sub.4z).
 In general, complexes of compounds of formulae (Ia) and/or (Ib) typically
 include two compounds having at least one metal cation positioned
 therebetween. The metal cation bonds with various appropriate lone pair or
 electron donating sites on the two compounds, namely oxygen and nitrogen
 atoms with respect to such compounds. In various preferred embodiments,
 such complexes also include at least one "solvent residue" which is
 obtained from one or more solvents set forth herein. In such complexes,
 the solvent residue is bound to the metal cation and the nitrogen present
 on the benzimidazole portion of the compounds. Examples of suitable
 solvent residues include, without limitation, alkoxides (e.g., lower
 (C.sub.1 to C.sub.4) alkoxides) with ethoxide being preferred.
 The ratio of metal cation to compound in a complex of the invention
 typically depends on the specific structure of the compound and the
 valence of the metal cation. In embodiments employing a solvent residue,
 the amount of such residue that is employed will typically depend on the
 above factors as well as the type of residue used. In preferred
 embodiments, the ratio of: (1) compounds of formulae (Ia) and/or (Ib) as
 defined by any of compounds (Iai), (Iaii), (Iaiii), (Iaiv), (Ibi), (Ibii),
 (Ibiii), and (Ibiv), respectively, or combinations thereof; to (2) one or
 more metal cation; to (3) solvent residue will typically be 2:1:1 or 2:2:2
 respectively. Other ratios may be required depending on the change of the
 cation and the type of complex embodiment.
 In various embodiments, the compositions comprising the complexes may be
 essentially free from compounds represented by formula (Ib), as defined
 herein.
 In these embodiments, the term "essentially free from" preferably refers to
 such complexes formed with sodium as the metal cation comprising at least
 about 95 percent (w/w) of the compound represented by formula (Ia).
 The compositions comprising the complexes described above preferably are in
 crystalline form.
 In certain embodiments, the compositions comprising the complexes may
 employ the diastereomers of the compounds represented by formula (Ia), and
 if applicable, the compounds represented by formula (Ib) according to any
 of the embodiments set forth hereinabove. In one non-limiting embodiment,
 for example, the concentration of compounds having the combination of the
 diastereomers S.sub.xa --R.sub.4z and S.sub.xb --R.sub.4q is from about 50
 percent (w/w) to about 100 percent (w/w) of the composition, and the
 concentration of the compounds having the diastereomers S.sub.xa
 --R.sub.4q and S.sub.xb --R.sub.4z is from about 0 percent (w/w) to about
 50 percent (w/w) of the composition, such that the sum of the total
 concentration of all such compounds is about 100 percent (w/w).
 Preferably, the concentration of such compounds having the combination of
 diastereomer pairs S.sub.xa --R.sub.4z and S.sub.xa --R.sup.4q is greater
 than about 70 percent.
 Hydrates and solvates of the compounds of formulas (Ia) and (Ib) along with
 polymorphs thereof are also provided by the invention and may be formed
 according to techniques known to one having ordinary skill in the
 pharmaceutical arts. As an example, solvates of any embodiments
 encompassing the compounds represented by formula (Ia) may be made
 according to known techniques. Suitable solvents for use in providing the
 solvates are known in the art and may vary according to the particular
 embodiment. Exemplary solvents include hydrates alcohols, such as, without
 limitation, methanol, ethanol, and the like.
 The invention also pertains to methods for providing each of the
 diastereomers S--S, S--R, R--S, and R--R of the compounds of formulae (Ia)
 and/or (Ib), or pairs thereof, in resolved form. Preferably, in various
 embodiments, each diastereomer pair of compounds (Ia) and/or (Ib) are
 essentially free of the three other diastereomers, or combinations
 thereof, e.g., at least 95 percent (w/w).
 As set forth herein, the compounds of (Ia) and (Ib) have been discovered to
 exhibit chirality at two distinct locations: (1) an atomic chiral center
 located at each sulfoxide group (as referenced by the first letter denoted
 in the diastereomer pair designation) and (2) a structural chiral center
 (i.e., a chiral plane) located at each pyridinal moiety on the compound
 (as referenced by the second letter denoted in the diastereomer pair
 designation). A preferred method for resolving each of the above
 diastereomer pairs involves first resolving the structural chiral center
 of the various materials used in making compounds (Ia) and/or (Ib)
 including those set forth herein. For example, the starting pyridine
 compound may be resolved at the R.sub.4 position referred to herein, or
 alternatively one of the pyridinal-moiety containing intermediates can be
 resolved at the R.sub.4 position such as, for example, a thiol compound
 represented by formulae (II) or (VIII). In this instance, the resolution
 of the thiol compound is carried out prior to oxidation which eventually
 forms compound (Ia) and/or (Ib). The actual techniques for resolving the
 structural chiral centers may be carried out by various suitable methods.
 Subsequent to oxidation, the materials used in making the compounds (Ia)
 and/or (Ib) are then be resolved at the atomic chiral center eventually
 providing each of the resolved diastereomer pairs of compounds (Ia) and/or
 (Ib). Any number of techniques may be used to resolve the atomic chiral
 center of these compounds, e.g., recrystallization from an optically
 active solvent, use of microorganisms, reactions with optically active
 acids forming salts which can be separated based on different solubilities
 of the diastereomers. Suitable optically active acids are, for example,
 the L- and D-forms of tartaric acid, di-o-tolyl-tartaric acid, malic acid,
 mandelic acid, camphorsulfonic acid or quinic acid.
 In one embodiment, atomic chiral center resolution of the compounds of
 formulae (Ia) and (Ib) may be obtained by chromatographic techniques.
 Materials that may be used in this method include a cellulose (e.g.,
 triphenylcarbamoyl- cellulose) coated on a column that includes a
 silica-containing material (e.g., silica or 3-aminopropyl silica). The
 column may be prepared by suspension in an organic solvent (e.g., methanol
 or 2-propanol) using an appropriate technique such as, for example, a
 descending slurry-packing technique.
 Mobile phases for use in this procedure can be prepared by various methods,
 such as, for example, using n-hexane and diethylamine in different ratios.
 Other materials, however, may be employed such as, without limitation,
 alcohols (e.g., methanol, ethanol). The compounds of formula (Ia) and (Ib)
 may be combined in the mobile phase along with other components known in
 the art such as, for example, a suitable buffer (e.g., a phosphate
 compound). The mobile phase is then passed through the column under
 processing (e.g., temperature, flow, and pressure) conditions that may be
 set by the operator. The diastereomer that first eluted from the column
 can be isolated by evaporation of the solvents. The diastereomer can be
 deemed isolated by known analytical techniques.
 In another embodiment, the formation of compounds of formulae (Ia) and/or
 (Ib) having resolved atomic chiral centers may be formed by carrying out
 the asymmetric oxidation in an organic solvent of a pro-chiral sulphide
 according to the formula (X):
 ##STR35##
 wherein R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are defined
 above with R being present in the 6- or 5-position, with an oxidizing
 agent and a chiral titanium complex, optionally in the presence of a base.
 A number of oxidizing agents may be employed such as, for example, a
 hydroperoxide, more particularly tert-butylhydroperoxide or cumene
 hydroperoxide.
 The titanium complex suitable for use in the reaction may be prepared using
 various methods. In one embodiment, the titanium complex is prepared from
 a chiral ligand and a titanium (IV) compound such as, for example,
 preferably titanium(IV) alkoxide, and optionally in the presence of water.
 An especially preferred titanium (IV) alkoxide is titanium (IV)
 isoperoxide or isopropoxide. Various amounts of chiral titanium complex
 may be used. Typically, an amount less than approximately about 0.50
 equivalents is preferred and an especially preferred amount is about 0.05
 to about 0.30 equivalents.
 The titanium complex may also be prepared by reacting titanium
 tetrachloride with a chiral ligand in the presence of a base. The chiral
 ligand used in the preparation of the titanium complex is typically a
 branched or unbranched alkyl diol, or an aromatic diol. Preferred chiral
 diols are, for example, esters of tartaric acid, especially (+)-diethyl
 L-tartrate or (-)-diethyl D-tartrate. It should be noted that the titanium
 complex may be prepared in the presence of the compound of formula (X) or
 before the compound of formula (X) is added to the reaction vessel.
 The oxidation is preferably carried out in the presence of a base. For
 example, the base may be an inorganic or organic base, such as, but not
 limited to, a hydrogen carbonate, an amide, or an amine such as guanidine
 or an amidine. Examples of other bases include triethylamine or
 N,N-diisopropylethylamine.
 The oxidation is typically carried out in the presence of an organic
 solvent. The solvent can be selected with respect to suitable conditions.
 Suitable organic solvents include, but are not limited to, toluene, ethyl
 acetate, methyl ethyl ketone, methyl isobutyl ketone, diethyl carbonate,
 tert butyl methyl ether, tetra hydrofuran, methylene chloride, and the
 like, and blends and mixtures thereof.
 The oxidation is preferably carried out in the organic solvent at room
 temperature or just above room temperature, e.g., between about 20.degree.
 C. and about 40.degree. C. It is believed that the reaction times may be
 longer if the reaction is carried out below 20.degree. C. The temperature
 of the reaction may be varied according to the intentions of one skilled
 in the art.
 The products formed during the oxidation reaction may be extracted with an
 aqueous solution of ammonia or another N-containing base to avoid
 precipitation and/or formation of insoluble titanium salts. The aqueous
 phase is separated from the organic phase of the obtained mixture and the
 isolated aqueous phase is neutralized by the addition of a neutralizing
 agent resulting in the protonation of the diastereomers. The diastereomers
 may be extracted by an organic solvent. They may also be crystallized in
 an organic or aqueous solvent resulting in the desired resolved
 diastereomers of compounds (Ia) and/or (Ib) In addition to using the above
 techniques to provide individual diastereomers S.sub.xa --R.sub.4q,
 S.sub.xa --R.sub.4z, S.sub.xb --R.sub.4q, and S.sub.xb --R.sub.4z, these
 techniques may be used to provide various combinations of diastereomers as
 set forth herein, including, without limitation, those which are
 essentially free from other diastereomers.
 The invention also provides for methods of making salts of diastereomers
 and pairs thereof. A preferred method for making the salts of the
 individual diastereomers and/or pairs thereof first involves forming these
 diastereomers of pairs thereof according to the teachings of the preceding
 section, in which the chiral plane is first resolved followed by
 resolution of the sulfoxide atomic chiral center. Salts of these resolved
 diastereomers or pairs thereof may then be formed according to various
 techniques.
 Examples of salts of diastereomers or pairs thereof that may be obtained
 include, but are not limited to, alkali and alkaline metal salts. As an
 example, to obtain optically pure alkali salts of the compounds of
 formulae (Ia) and/or (Ib), the diastereomer obtained in a manner described
 herein, may be treated with: (1) a base, such as for example,
 M.sub.1.sup.+ OH wherein M.sub.1 is sodium, ammonium, potassium, or
 lithium, in a aqueous or nonaqueous medium; (2) M.sub.1.sup.+ OR.sup.2
 wherein M.sub.1.sup.+ is defined above, and R.sup.2 is an alkyl group
 containing 1 to 4 carbon atoms; or (3) M.sub.1.sup.+ NH.sub.2 wherein
 M.sub.1.sup.+ is defined above. In order to obtain the crystalline form of
 the alkali salts, addition of the base M.sub.1.sup.+ OH in a non-aqueous
 medium such as a mixture of 2-butanone and toluene, is preferred.
 To obtain an optically pure alkaline metal salt of a diastereomer or pair
 thereof of the compounds of formulae (Ia) and/or (Ib), the optically pure
 alkali salt is treated with an aqueous solution of an inorganic alkaline
 metal salt such as, for example, M.sub.2.sup.2+ Cl.sub.2 wherein
 M.sub.2.sup.2+ is an alkaline metal such as calcium, magnesium, strontium,
 barium, and the like, whereupon the alkaline metal salt of the single
 enantiomer is precipitated. The optically pure alkaline metal salts may
 also be prepared by treating a single enantiomer of compounds of formula
 (Ia) and/or (Ib) with a base such as, for example, M.sub.2.sup.2+
 (OR.sup.3).sub.2 wherein R.sup.3 is an alkyl group containing 1 to 4
 carbon atoms, in a non-aqueous solvent such as alcohol (for alcoholates),
 e.g., ROH, or in an ether such as tetrahydrofuran.
 A preferred embodiment for the preparation of the magnesium salts of the
 S--S or S--R diastereomer or pairs thereof of the compounds of formulae
 (Ia) and/or (Ib) polyhydrates comprises: a) treating a magnesium salt of
 the above individual diastereomer or pairs thereof of such compounds with
 water at a suitable temperature for a suitable time. The phrase "a
 suitable temperature" means a temperature which induces the transformation
 of starting material to product without decomposing any of these
 compounds. Examples of such suitable temperatures include, but are not
 limited to, ambient temperature and above. By a suitable time is meant a
 time that results in high conversion of the starting material into product
 without causing any decomposition of either compound, i.e., results in a
 good yield. This suitable time will vary depending on the temperature used
 in a way well known to people in the art. By increasing the temperature,
 less time is required to give the desired conversion. The amount of water
 is generally not crucial and will depend on the process conditions used.
 The magnesium salts of the above diastereomers or pairs thereof of the
 compounds of formulae (Ia) and/or (Ib) polyhydrates is thereafter
 separated from the aqueous slurry, for example by filtration or
 centrifugation and thereafter dried to constant weight.
 Optionally, the process may comprise: b) oxidizing compounds of formula
 (II) defined herein, with an oxidizing agent and a chiral titanium
 complex, optionally in the presence of a base. The oxidation is carried
 out in an organic solvent, for example toluene or dichloromethane. The
 crude product is then converted to the corresponding potassium salt by
 treatment with a potassium source, such as methanolic potassium hydroxide
 or methanolic potassium methylate, followed by isolation of the formed
 salt.
 The resulting potassium salts of the S--S or S--R diastereomers, or
 combinations thereof, of the compounds of formulae (Ia) and/or (Ib) are
 thereafter converted to the corresponding magnesium salts by treatment
 with a magnesium source, such as, for example, magnesium sulfate in a
 lower alkyl alcohol, such as methanol. The solution is optionally filtered
 and the precipitation is initialized by addition of a non-solvent such as
 acetone. The product is filtered off and optionally washed with water and
 further processed as is described in a) above. Alternatively, the
 potassium salts may be treated with a magnesium source, such as, for
 example, magnesium sulfate in water, and isolation of the magnesium salts
 of the S--S or S--R diastereomers or pairs thereof of the compounds of
 formula (Ia) and (Ib) polyhydrates, or any other conventional technique
 for transforming a potassium salt to the corresponding magnesium salt can
 be used.
 The potassium salts of the S--R or S--S diastereomers, or pairs thereof, of
 the compounds of formulas (Ia) and (Ib) are suitable intermediates in the
 preparation of the magnesium salts of these diastereomers or pairs
 thereof. The potassium salts of these diastereomers may also be used as
 active components in pharmaceutical formulations to be used in the
 treatment of various diseases described herein, particularly
 gastrointestinal diseases.
 The present invention also encompasses pharmaceutical formulations
 comprising at least one active pharmaceutical ingredient of the present
 invention and at least one pharmaceutically acceptable carrier, diluent,
 or excipient, the selection of which are known to the skilled artisan. For
 the purposes of the invention, the term "active ingredient" refers to any
 of the embodiments set forth herein referring to the compound(s) of
 formula (Ia) and/or (Ib), diastereomers thereof, any combinations of
 diastereomers thereof, pharmaceutically acceptable salts thereof, along
 with complexes, hydrates, solvates, and polymorphs of any of the above, as
 well as any compositions thereof. Prodrugs of any of these active
 pharmaceutical ingredients may also be employed for the purposes of the
 invention, most preferably as part of a pharmaceutical formulation,
 although their use in other embodiments may be carried out. The term
 "active ingredient" also encompasses, in one embodiment, a solid
 pharmaceutical composition of the present invention which is blended with
 at least one pharmaceutically acceptable excipient, diluted by an
 excipient or enclosed within such a carrier which can be in the form of a
 capsule, sachet, tablet, buccal, lozenge, paper, or other container. When
 the excipient serves as a diluent, it may be a solid, semi-solid, or
 liquid material which acts as a vehicle, carrier, or medium for the active
 ingredient. Thus, the formulations can be in the form of tablets, pills,
 powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard
 gelatin capsules, suppositories, sterile injectable solutions, and sterile
 packaged powders.
 Examples of suitable excipients include, but are not limited to, starches,
 gum arabic, calcium silicate, microcrystalline cellulose,
 polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The
 formulations can additionally include lubricating agents such as, for
 example, talc, magnesium stearate and mineral oil; wetting agents;
 emulsifying and suspending agents; preserving agents such as methyl- and
 propyl hydroxybenzoates; sweetening agents; or flavoring agents. Polyols,
 buffers, and inert fillers may also be used. Examples of polyols include,
 but are not limited to: mannitol, sorbitol, xylitol, sucrose, maltose,
 glucose, lactose, dextrose, and the like. Suitable buffers encompass, but
 are not limited to, phosphate, citrate, tartarate, succinate, and the
 like. Other inert fillers which may be used encompass those which are
 known in the art and are useful in the manufacture of various dosage
 forms. If desired, the solid pharmaceutical compositions may include other
 components such as bulking agents and/or granulating agents, and the like.
 The compositions of the invention can be formulated so as to provide
 quick, sustained, or delayed release of the active ingredient after
 administration to the patient by employing procedures well known in the
 art.
 In the event that the above formulations are to be used for parenteral
 administration, such a formulation typically comprises sterile aqueous and
 non-aqueous injection solutions comprising the active ingredient, which
 preparations are preferably isotonic with the blood of the intended
 recipient. These preparations may contain anti-oxidants, buffers,
 bacteriostats, and solutes which render the formulation isotonic with the
 blood of the intended recipient. Aqueous and non-aqueous sterile
 suspensions may include suspending agents and thickening agents. The
 formulations may be presented in unit-dose or multi-dose containers, for
 example sealed ampules and vials. Extemporaneous injection solutions and
 suspensions may be prepared from sterile powders, granules and tablets of
 the kind previously described.
 In certain embodiments of the invention, the active ingredient may be made
 into the form of dosage units for oral administration. The active
 ingredient may be mixed with a solid, pulverant carrier such as, for
 example, lactose, saccharose, sorbitol, mannitol, starch, amylopectin,
 cellulose derivatives or gelatin, as well as with an antifriction agent
 such as, for example, magnesium stearate, calcium stearate, and
 polyethylene glycol waxes. The mixture is then pressed into tablets. If
 coated tablets are desired, the above prepared core may be coated with a
 concentrated solution of sugar, which may contain gum arabic, gelatin,
 talc, titanium dioxide, or with a lacquer dissolved in volatile organic
 solvent or mixture of solvents. To this coating various dyes may be added
 in order to distinguish among tablets with different active compounds or
 with different amounts of the active compound present.
 Soft gelatin capsules may be prepared in which capsules contain a mixture
 of the active ingredient and vegetable oil. Hard gelatin capsules may
 contain granules of the active ingredient in combination with a solid,
 pulverulent carrier, such as, for example, lactose, saccharose, sorbitol,
 mannitol, potato starch, corn starch, amylopectin, cellulose derivatives,
 or gelatin.
 Dosage units for rectal administration may be prepared in the form of
 suppositories which may contain the active ingredient in a mixture with a
 neutral fat base, or they may be prepared in the form of gelatin-rectal
 capsules which contain the active substance in a mixture with a vegetable
 oil or paraffin oil.
 Liquid preparations for oral administration may be prepared in the form of
 syrups or suspensions, e.g., solutions containing an active ingredient,
 sugar, and a mixture of ethanol, water, glycerol, and propylene glycol. If
 desired, such liquid preparations may contain coloring agents, flavoring
 agents, and saccharin. Thickening agents such as carboxymethylcellulose
 may also be used.
 Solutions for parenteral administration by injection may be prepared as an
 aqueous solution of a water soluble pharmaceutically acceptable salt of
 the active ingredient. These solutions may also contain stabilizing agents
 and/or buffering agents and may be manufactured in different dosage unit
 ampules.
 Tablets for oral use are typically prepared in the following manner,
 although othertechniques may be employed. The solid substances are ground
 or sieved to a desired particle size, and the binding agent is homogenized
 and suspended in a suitable solvent. The active ingredient and auxiliary
 agents are mixed with the binding agent solution. The resulting mixture is
 moistened to form a uniform suspension. The moistening typically causes
 the particles to aggregate slightly, and the resulting mass is pressed
 through a stainless steel sieve having a desired size. The layers of the
 mixture are then dried in controlled drying units for determined length of
 time to achieve a desired particle size and consistency. The granules of
 the dried mixture are sieved to remove any powder. To this mixture,
 disintegrating, aniffriction, and anti-adhesive agents are added. Finally,
 the mixture is pressed into tablets using a machine with the appropriate
 punches and dies to obtain the desired tablet size. The operating
 parameters of the machine may be selected by the skilled artisan.
 Typically, preparation of lozenge and buccal dosage forms are prepared by
 methods known to one of ordinary skill in the art.
 In a particular embodiment, the active ingredient may be present in a core
 surrounded by one or more layers including an enteric coating layer. With
 respect to formation of the core, the active ingredient is typically mixed
 with inert, preferably water soluble, conventional pharmaceutically
 acceptable constituents to obtain the preferred concentration of the
 active ingredient in the final mixture with an alkaline reacting,
 otherwise inert, pharmaceutically acceptable substance (or substances),
 which creates a "micro-pH" around each particle of active compound of not
 less than a pH of 7, preferably not less than a pH of 8, when water is
 adsorbed to the particles of the mixture or when water is added in small
 amounts to the mixture. Such substances can be chosen among, but are not
 limited to, sodium, potassium, calcium, magnesium, and aluminum salts of
 phosphoric acid, carbonic acid, citric acid, or other suitable weak
 inorganic or organic acids; substances typically used in antacid
 preparations such as aluminum, calcium, and magnesium hydroxides;
 magnesium oxide or composite substances such as, for example, Al.sub.2
 O.sub.3. 6MgO CO.sub.2.12H.sub.2 O(Mg.sub.6 Al.sub.2.(OH).sub.16 CO.sub.3
 4H.sub.2 O), MgO.Al.sub.2 O.sub.3, 2SiO.sub.2.nH.sub.2 O, wherein n is not
 necessarily an integer and may be less than 2, or similar compounds;
 organic pH-buffering substances such as trihydroxymethylamino-methane or
 other similar, pharmaceutically acceptable pH-buffering substances. The
 stabilizing high pH-value in the powder mixture can also be achieved by
 using an alkaline reacting salt of the active compound such as, but not
 limited to, sodium, potassium, magnesium, and calcium salts of active
 ingredient, either alone or in combination with a conventional buffering
 substance as previously described.
 The powder mixture may then be formulated into small beads, i.e., pellets
 or tablets, by conventional pharmaceutical procedures. The pellets,
 tablets, or gelatin capsules may then be used as cores for further
 processing.
 The reacting cores containing the active ingredient may be separated from
 the enteric coating polymer(s) containing free carboxyl groups, which
 otherwise is capable of causing degradation/discoloration of the active
 compound during the coating process or during storage. The subcoating
 layer (i.e., the separating layer), also serves as a pH-buffering zone in
 which hydrogen ions diffusing from the outside in towards the core can
 react with hydroxyl ions diffusing from the core towards the surface of
 the coated article. The pH-buffering properties of the separating layer
 can be further strengthened by introducing in the layer substances chosen
 from a group of compounds usually used in antacid formulations described
 above. The separating layer usually consists of one or more water soluble
 inert layers, optionally containing pH-buffering substances.
 The separating layer(s) can be applied to the cores, typically in the form
 of pellets or tablets, by conventional coating procedures in a suitable
 coating pan or in a fluidized bed apparatus using water and/or
 conventional organic solvents for the coating solution. The material for
 the separating layer may be chosen among the pharmaceutically acceptable
 water soluble, inert compounds or polymers used for film-coating
 applications such as, for example, sugar, polyethylene glycol,
 polyvinylpyrrollidone, polyvinyl alcohol, hydroxypropyl cellulose,
 hydroxymethyl cellulose, hydroxypropyl methylcellulose, or the like. The
 thickness of the separating layer may be determined according to the
 skilled artisan.
 In the case of tablets, another method to apply the coating can be
 performed by the dry coating technique. First, a tablet containing the
 active ingredient is compressed as described herein. Around this tablet,
 another layer is compressed using a suitable tableting technique machine.
 The outer, separating layer, contains pharmaceutically acceptable, in
 water soluble or in water, rapidly disintegrating tablet excipients.
 Conventional plasticizers, pigments, titanium dioxide talc, and other
 additives may be included in the separating layer. In embodiments
 encompassing gelatin capsules, the gelatin capsule itself serves as a
 separating layer.
 The enteric coating layer is typically applied on to the sub-coated cores
 by conventional coating techniques such as, for example, pan coating or
 fluidized bed coating using solutions of polymers in water and/or suitable
 organic solvents or by using latex suspensions of the polymers. Enteric
 coating polymers that can be used include, for example, cellulose acetate
 phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate
 phthalate, carboxymethylethylcellulose, co-polymerized methacrylic
 acid/methacrylic acid methyl esters such as, for example, compounds known
 under the trade name Eudragit.RTM.L 12,5 or Eudragit.RTM.L 100 (Rohm
 Pharma of Darmstadt, Germany), or other similar compounds. The enteric
 coating can also be applied using water-based polymer dispersions, e.g.
 Aquateric.RTM.(FMC Corporation of Chicago, Ill.), Eudragit.RTM.L100-55
 (Rohm Pharma of Darmstadt, Germany), Coating CE 5142 (BASF of Mount Olive,
 N.J). The enteric coating layer can optionally contain a pharmaceutically
 acceptable plasticizer such as, for instance, cetanol, triacetin, citric
 acid esters such as, for example, those known under the trade name
 Citroflex.RTM. (Pfizer of New York, N.Y.), phthalic acid esters, dibutyl
 succinate or similar plasticizers. The amount of plasticizer is usually
 optimized for each enteric coating polymer(s). Dispersants such as talc,
 colorants and pigments may also be included into the enteric coating
 layer.
 Thus, the formulations described by the above embodiments comprise cores
 containing at least one active ingredient described herein, optionally
 mixed with an alkaline reacting compound, or cores comprising a salt of at
 least one active ingredient or one or more enantiomers thereof as taught
 herein, or at least one pharmaceutically acceptable salt, hydrate,
 solvate, or polymorph thereof, optionally mixed with an alkaline reacting
 compound. The alkaline reacting core material and/or alkaline salt of the
 active ingredient is believed to potentially enhance the stability of the
 active ingredient. The cores suspended in water form a solution or a
 suspension which has a pH which is higher than that of a solution in which
 the polymer used for enteric coating is just soluble. The cores may be
 coated with an inert reacting water soluble or in water rapidly
 disintegrating coating, optionally containing a pH-buffering substance,
 which separates the cores from the enteric coating. Without this
 separating layer, the resistance towards gastric juice may be too short
 and/or the storage stability of the dosage form would be unacceptably
 short. The sub-coated dosage form is finally coated with an enteric
 coating rendering the dosage form insoluble in acid media, but rapidly
 disintegrating/dissolving in neutral to alkaline media such as, for
 instance, the liquids present in the proximal part of the small intestine.
 The final dosage form encompassing the above embodiments may be either an
 enteric coated tablet or capsule or in the case of enteric coated pellets,
 pellets dispensed in hard gelatin capsules or sachets or pellets
 formulated into tablets. It is desirable for the long term stability
 during storage that the water content of the final dosage form containing
 the active ingredient (enteric coated tablets, capsules or pellets) be
 kept low. As a consequence, the final package containing hard gelatin
 capsules filled with enteric coated pellets preferably also contain a
 desiccant, which reduces the water content of the gelatin shell to a level
 where the water content of the enteric coated pellets filled in the
 capsules does not exceed a certain level.
 The invention also provides methods of treating a subject (e.g., mammal,
 particularly humans) comprising administering to a subject in need of such
 treatment a therapeutically effective amount of at least one active
 ingredient described above. The active ingredient(s) may be used to treat
 a number of disorders. Generally, the compound is useful for preventing
 and treating gastric acid related diseases in mammals and particularly
 humans. These diseases include, but may not be limited to, duodenal ulcer,
 H. pylori infection, gastric ulcer, gastro-esophageal reflux disease and
 symptoms associated therewith (e.g., heartburn), erosive esophagitis,
 pathological hypersecretary conditions (e.g., Zollinger-Ellison syndrome,
 endocrine adenomas and systematic mastocytosis), gastritis, duodenitis.
 The active ingredient(s) may also be used for the treatment of other
 gastrointestinal disorders where gastric acid inhibitory effect is
 desirable (e.g., in patients on NSAID therapy, in patients with Non Ulcer
 Dyspepsia). The active ingredient(s) may also be used in patients in
 intensive care situations, in patients with acute upper gastrointestinal
 bleeding, pre- and post-operatively to prevent acid aspiration of gastric
 acid and to prevent and treat stress ulceration. Moreover, the active
 ingredient(s) may be useful in the treatment of psoriasis as well as in
 the treatment of Heliocobacter infections and diseases related to those.
 The active ingredient(s) may also be used for the treatment or
 "prophylaxis" of inflammatory conditions in mammals and particularly
 humans, particularly those involving lysozymal enzymes. As used herein,
 the term "treatment", or a derivative thereof, contemplates partial or
 complete inhibition of the stated disease state such as, for example,
 pain, when a composition of the present invention is administered
 prophylactically or following the onset of the disease state for which
 such composition of the present invention is administered. For the
 purposes of the invention, "prophylaxis" refers to administration of the
 active ingredient(s) to a mammal to protect the mammal from any of the
 disorders set forth herein, as well as others. Other examples of such
 conditions that may be treated include rheumatoid arthritis and gout.
 Other disorders that may be prevented or treated in accordance with the
 invention including schizophrenia, symptoms of bradyphremia in Parkinson's
 Disease, elevated intraocular pressure in the eye of a patient, and
 microbial infections associated with gram-negative bacteria (especially
 microaerophilic bacteria), bacteria of the genus Campylbacter represented
 by C. pylon. The treatment of infectious diseases due to such bacteria in
 mammalian animals including without limitation humans, cattle, horse, dog,
 mouse, rat, the control and inhibition of environmental pollution, and
 disinfectant use may be achieved by virtue of the invention.
 The active ingredient(s) disclosed herein possess worthwhile therapeutic
 properties as gastric acid secretion inhibitors as demonstrated by the
 following tests. To determine the gastric acid secretion inhibitory
 properties, experiments are performed on conscious dogs provided with
 gastric fistulas of conventional type and duodenal fistulas, the latter
 ones used for direct intraduodenal administration of the active
 ingredient(s). After 18 hours starvation and deprivation of water the dogs
 are given a subcutaneous infusion of pentagastrin (1-4 nmol/kg, h) lasting
 for 6 to 7 hours. Gastric juice is collected in consecutive 30 minute
 samples. An aliquot of each sample is titrated with 0.1 N NaOH to pH 7 for
 titrable acid concentration using an automatic titrator and pH-meter. Acid
 output is calculated as mmol H +/60 minutes. The active ingredient(s),
 suspended in 0.5 percent methyl cellulose, is given intraduodenally in
 doses from 4 to 20 .mu.mol/kg when the secretory response to pentagastrin
 reaches a steady level. This embodiment may also be used for prophylaxis
 by administration of the active ingredient prior to pentagastrin.
 The typical active daily dose of the active ingredients(s) will depend on
 various factors such as, for example, the individual requirement of each
 patient, the route of administration, and the disease. An attending
 physician may adjust the dosage rate based on these and other criteria if
 he or she so desires. As an example, a suitable oral dosage form may
 encompass from about 5 to about 360 mg total daily dose, typically
 administered in one single dose or equally divided doses. A more preferred
 range is from about 10 to about 60 mg total daily dose, and a most
 preferred range is from about 10 to about 40 mg total daily dose.
 Additionally, the active ingredient(s) may be administered in a solution,
 and, as an example, the daily doses set forth above may be employed. In
 one embodiment, the active ingredient(s) may be added in appropriate
 amounts to a solution such that the solution comprises, for example, from
 about 0.1 mg/ml to about 10 mg/ml of the active ingredient(s). It should
 be appreciated that daily doses other than those described above may be
 administered to a subject, as appreciated by an attending physician.
 The following examples are intended to illustrate the invention, and are
 not to be construed as limiting the scope of the invention. For the
 purposes of the examples, the phrase "(5)6-methoxy
 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole"
 refers to a co-crystallized mixture of 5-methoxy
 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole
 and 6-methoxy
 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole.

EXAMPLE 1
 Preparation of Pure 6-methoxy
 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole
 Approximately 850 mL of methanol was placed in a 1 liter glass bottle with
 a screw cap. The solution was saturated by dissolving approximately 10.5
 grams of (5)6-methoxy
 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole,
 and the resulting solution was stirred. Once the solution was saturated,
 an additional 17 grams of (5)6-methoxy
 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole
 was added to the saturated solution to create a suspension. The cap was
 sealed and the saturated suspension was allowed to stir and equilibrate
 for about four days.
 After four days, the suspension was filtered through a paper filter and
 then washed with a small amount of methanol. The supernatant was returned
 to the 1 liter glass bottle and an additional 10 grams of (5)6-methoxy
 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1-H-benzimidazole
 was added to the saturated solution. The procedure was repeated to create
 an additional sample. All samples were shown to be pure 6-methoxy
 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole
 by X-ray powder diffraction.
 EXAMPLE 2
 Preparation of Essentially Pure (5)6-methoxy
 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole
 To a 50 mL beaker was added about 1 g of (5)6-methoxy 2-[(4-methoxy-3,5
 dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole to 30 mL of
 dimethylformamide (DMF). Additional (5)6-methoxy
 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole
 was added to the resulting solution until a suspension of the material was
 formed. The solution was stirred for approximately 10 minutes, and then
 filtered through a 0.45 .mu.m Poly(tetrafluoroethylene) (PTFE) or Nylon
 filter. The resulting saturated solution was placed in a shallow petrie
 dish, covered and stored under refrigerated conditions (approximately
 5.degree. C.) until crystals formed (between 4-6 days). The identity of
 the title compound was confirmed by single crystal x-ray diffraction, and
 shown to contain about 97 percent (w/w) of the 6-methoxy
 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole
 and about 3 percent (w/w) of 5-methoxy
 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole.
 EXAMPLE 3
 Preparation of (5)6-methoxy
 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole
 The procedure set forth in Example 2 is repeated except that ethanol is
 employed as a solvent in place of DMF and the resulting structure was
 shown by various X-ray crystal diffraction to contain 83 percent (w/w) of
 6-methoxy
 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole
 and 17 percent (w/w) of 5-methoxy
 2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole.
 EXAMPLE 4
 Preparation of
 5(6)-methoxy-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benz
 imidazole Isomers
 To a 50 mL beaker was added about 1 g of
 5(6)-methoxy-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benz
 imidazole to 30 mL of DMF. Additional
 5(6)-methoxy-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benz
 imidazole was added to the resulting solution until a suspension of the
 material was formed. The solution was stirred for approximately 10
 minutes, and then filtered through a 0.45 .mu.m PTFE or Nylon filter. The
 resulting saturated solution was placed in a shallow petrie dish, covered,
 and stored at ambient temperature until crystals formed (between 1-2
 days). The identity of the title compound was confirmed by single crystal
 x-ray diffraction. The resulting structure was determined to contain about
 93 percent (w/w) of the 6-methoxy isomer and about 7 percent (w/w) of the
 5-methoxy isomer.
 EXAMPLE 5
 Preparation of
 5(6)-methoxy-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benz
 imidazole Isomers
 To a 50 mL beaker was added about 1 g of
 5(6)-methoxy-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benz
 imidazole to 30 mL of methylene chloride. Additional
 5(6)-methoxy-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benz
 imidazole was added to the resulting solution until a suspension of the
 material was formed. The solution was stirred for approximately 10
 minutes, and then filtered through a 0.45 .mu.m PTFE or Nylon filter. The
 resulting saturated solution was placed in a beaker, covered, and stored
 under refrigerated conditions (approximately 5.degree. C.) until crystals
 formed (between 1-2 days). The identity of the title compound was
 confirmed by single crystal x-ray diffraction. The resulting structure was
 determined to contain about 88 percent (w/w) of the 6-methoxy isomer and
 about 12 percent (w/w) of the 5-methoxy isomer.
 EXAMPLE 6
 Preparation of
 5(6)-methoxy-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benz
 imidazole Isomers
 To a 50 mL beaker was added about 1 g of
 5(6)-methoxy-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benz
 imidazole to 25 mL of acetone. Additional
 5(6)-methoxy-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benz
 imidazole was added to the resulting solution until a suspension of the
 material was formed. The solution was stirred for approximately 5 minutes,
 and then filtered through a 0.45 .mu.m PTFE or Nylon filter. The resulting
 saturated solution was placed in a 50 mL beaker, covered, and stored at
 ambient temperature until crystals formed (between 1-2 days). The identity
 of the title compound was confirmed by single crystal x-ray diffraction.
 The resulting structure was determined to contain about 86 percent (w/w)
 of the 6-methoxy isomer and about 14 percent (w/w) of the 5-methoxy
 isomer.
 EXAMPLE 7
 Preparation of
 5(6)-methoxy-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benz
 imidazole Isomers
 The procedure set forth in Example 6 is repeated except that an ACN/water
 mixture was used as a solvent in place of acetone. A similar composition
 of 5- and 6-methoxy isomers resulted.
 EXAMPLE 8
 Preparation of
 5(6)-methoxy-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benz
 imidazole Isomers
 The procedure set forth in Example 6 is repeated except that ACN was used
 as a solvent in place of acetone. A similar composition of 5- and
 6-methoxy isomers resulted.
 EXAMPLE 9
 Preparation of
 (5)6-methoxy-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benz
 imidazole Isomers
 To a 400 mL beaker was added about 5 g of
 (5)6-methoxy-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benz
 imidazole to 200 mL of ethanol. 1.0 mL of ammonium hydroxide was added to
 this solution and additional
 5(6)-methoxy-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benz
 imidazole was added to the resulting solution until a suspension of the
 material was formed. The solution was stirred for about 10 minutes, then
 filtered through a 0.45 .mu.m PTFE or Nylon filter. The resulting
 saturated solution was placed in two separate drying vessels, and stored
 in a fume hood at ambient temperature until crystals formed (between 1-12
 hours). The identity of the title compound was confirmed by single crystal
 x-ray diffraction. The resulting structure was determined to contain about
 82 percent (w/w) of the 6-methoxy isomer and about 18 percent (w/w) of the
 5-methoxy isomer.
 EXAMPLE 10
 Preparation of
 (5)6-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methy]Isulfinyl]-1H-b
 enzimidazole
 (5)6-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]suIfinyl]-1H-be
 nzimidazole (16.2 g; 0.0492 mol)) is reacted with m-chlorobenzoic acid
 (13.6 g; 0.0537 mol) with CH.sub.2 Cl.sub.2 acting as a solvent at a pH of
 8.6. The pH is maintained by the presence of KHCO.sub.3 (5.6 g; 0.056 mol)
 acting as a buffer. The temperature is maintained at about 0.degree. C.
 during the addition. Diluted NaOH is added to a pH above 12 and the
 CH.sub.2 Cl.sub.2 phase is separated off. Dimethylformamide (4.7 g) is
 charged to the water phase and the pH is kept above 9, whereupon a mixture
 of
 (5)6-methoxy-2[(4-methoxy-3,5-diemthyl-2-pyridinyl)-methylsulfinyl]-1H-ben
 zimidazole is formed. The crystals are filtered off and are washed with
 water and methanol at a temperature of about 0.degree. C. The washed
 crystals are then dried under vacuum and are found to predominantly
 contain
 6-methoxy-2[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzim
 idazole.
 EXAMPLE 11
 Preparation of the Sodium Salt of
 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz
 imidazole
 To a stirring suspension of 10 g (29 mmol) of
 (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-b
 enzimidazole in 200 mL of methyl ethyl ketone (MEK) in a 1 L flask was
 added at ambient temperature 6 mL of a 5 M aqueous sodium hydroxide
 solution. To that mixture was added 200 mL of toluene. After approximately
 7 minutes, the mixture became a clear solution. Approximately 2 minutes
 after that, the mixture became turbid again. This mixture was allowed to
 stir at ambient temperature overnight. The following morning, several
 crystals of
 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz
 imidazole sodium salt were added to act as seed crystals. Within a few
 minutes the product began to precipitate. After approximately 1 hour, the
 product was isolated by vacuum filtration through filter paper on a
 ceramic Buchner funnel and rinsed with 25 mL of diethyl ether. The
 resulting solids were allowed to air-dry for 24 hours.
 EXAMPLE 12
 Preparation of the Sodium Salt of
 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz
 imidazole
 To a flask containing 20 mL of methanol was slowly added with stirring 580
 mg (14.48 mmol) of 60% sodium hydride dispersed in mineral oil. The
 resulting cloudy mixture was vacuum filtered through a glass-fiber filter
 paper to yield a clear solution. To this clear solution was added with
 stirring 5 g (14.48 mmol) of
 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz
 imidazole. After approximately 5 minutes of stirring, the solution became
 clear. The stirring was stopped, the flask was covered and set aside.
 After approximately 5 minutes, crystals began to form. The mixture was
 placed in a 5.degree. C.refrigerator overnight. The next day, the solids
 were isolated by vacuum filtration to give approximately 5 g of the
 desired product as a white, crystalline powder.
 EXAMPLE 13
 Preparation of the Sodium Salt of
 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz
 imidazole
 To a stirring solution of 5 g (14.48 mmol) of
 (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-b
 enzimidazole in 50 mL of dimethyl formamide (DMF) in a 100 mL beaker was
 slowly added at ambient temperature 580 mg (14.48 mmol) of 60% sodium
 hydride dispersed in mineral oil. Once all the sodium hydride was added,
 the mixture was allowed to stir for an additional 10 minutes. The solution
 was vacuum filtered through filter paper on a ceramic Buchner funnel. A 20
 mL portion of the resulting solution was placed in a 250 mL round-bottom
 flask, diluted with 50 mL of toluene and concentrated under reduced
 pressure at 20.degree. C. (2 times), followed by 50 mL of tetrahydrofuran
 (1 time). The resulting solids were dried 18 hours at ambient temperature
 in vacuo to yield the desired product as an off-white, crystalline powder.
 The powder was recrystallized from methanol by placing a filtered,
 saturated solution into the 5.degree. C. refrigerator for several days,
 until crystals were present.
 EXAMPLE 14
 Preparation of the Sodium Salt of
 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz
 imidazole
 To a stirring suspension of 5 g (14.48 mmol) of
 (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-b
 enzimidazole in 50 mL of tetrahydrofuran (THF) in a 100 mL beaker was
 slowly added at ambient temperature 580 mg (14.48 mmol) of 60% sodium
 hydride dispersed in mineral oil. Once all the sodium hydride was added,
 the mixture was allowed to stir for an additional 20 minutes. The solids
 were isolated by vacuum filtration through filter paper on a ceramic
 Buchner funnel and rinsed with a small amount of THF. The solids were
 dried 18 hours at ambient temperature in vacuo to yield 4.8 g (90%) of the
 desired product as an off-white, crystalline powder. The powder was
 recrystallized from 1:1 methanol:ethyl acetate by placing a filtered,
 saturated solution into the 5.degree. C. refrigerator for several days,
 until crystals were present.
 EXAMPLE 15
 Preparation of the Sodium Salt of
 (-)(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1
 H-benzimidazole
 To a stirring solution of 1.5 g (4.33 mmol) of
 (-)-(5)6-methoxy-2-[[(4-metyhoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]
 -1H-benzimidazole in 15 mL of tetrahydrofuran (THF) in a 50 mL beaker was
 slowly added at ambient temperature 173 mg of 60% sodium hydride dispersed
 in mineral oil. Once all the sodium hydride was added, the mixture was
 allowed to stir for 45 minutes at ambient temperature. An additional 15 mL
 of THF was added to the mixture and was allowed to stir for an additional
 20 minutes. The precipitated solids were isolated by vacuum filtration
 through filter paper on a ceramic Buchner funnel, rinsed with 40 mL of the
 THF and dried 18 hours at ambient temperature in vacuo to yield 1.3 g (81
 percent) of the desired product of an off-white powder.
 EXAMPLE 16
 Preparation of
 (+)-(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-
 1H-benzimidazole Sodium Salt
 To a stirring suspension of 650 mg (1.89 mmol) of
 (+)-(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-
 1H-benzimidazole in 6.5 mL of methyl ethyl ketone (MEK) in a 50 mL flask
 was added at ambient temperature 0.39 mL of a 5 M aqueous sodium hydroxide
 solution. To that mixture was added 13 mL of toluene. The resulting
 mixture was turbid, so an additional 6.5 mL of MEK was added and the
 mixture became a clear, yellow solution. This mixture was allowed to stir
 at ambient temperature overnight. The following morning, several crystals
 of
 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz
 imidazole sodium salt were added to act as seed crystals, but no product
 crystals formed. A stream of dry nitrogen gas was blown over the mixture
 to begin removing the solvent. After approximately 10 minutes, the product
 precipitated. The solids were isolated by vacuum filtration and washed
 with a small amount of diethyl ether. The solids were then placed into a
 vacuum desiccator to remove the last traces of ether, to yield
 approximately 500 mg of the desired product as an off-white powder.
 EXAMPLE 17
 Preparation of
 (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-b
 enzimidazole Magnesium Salt Tetrahydrate
 1.65 g of
 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz
 imidazole sodium salt was dissolved in 30 mL of water. To the stirring
 solution was added 0.47 g of magnesium chloride dissolved in 20 mL of
 water. Immediately upon the addition of the magnesium chloride solution a
 white powder precipitated. The suspension was allowed to stir for 5
 minutes, and then the product was isolated by vacuum filtration. The
 solids were then placed into a vacuum desiccator overnight to give the
 desired product as a white powder. A small portion of the powder was
 dissolved in methanol at about 75 mg/mL, filtered and diluted with a equal
 volume of water. This solution was partially covered and set aside to
 slowly evaporate. After approximately 5 days, crystals were isolated,
 analyzed by single crystal x-ray diffraction and shown to be the desired
 product.
 EXAMPLE 18
 Preparation of a Mixture of the (-) Enantiomers of (5)6-methoxy-2[[(4
 methoxy-3,5-diemthyl-2-pyridinyl)mrthyl]sulfinyl]-1H-benzimidazole
 (5)6-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimi
 dazole (4.0 g, 12.1 mmol) is suspended in toluene (12 mL). (-) Diethyl
 D-tartrate (0.17 mL, 1.0 mmol) and titanium(IV) isopropoxide (0.15 mL,
 0.50 mmol) are added with stirring at 50.degree. C. The mixture is stirred
 at 50.degree. C. for 50 minutes and then N,N-diisopropylethylamine(0.085
 mL, 0.50 mmol) is added at ca. 30.degree. C. Then, cumeme hydroperoxide
 (83%, 2.1 mL, 11.9 mmol) is added and the mixture is stirred for 15
 minutes at 30.degree. C. The resulting mixture contains the (-)
 enantiomers of (5)6 methoxy-2-[[(4-methoxy-3,5-d
 imethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole.
 EXAMPLE 19
 Preparation of a Mixture of the (+) Enantiomers of
 (5)6-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)mrthyl]sulfinyl]-1H-be
 nzimidazole
 (+) Diethyl L-tartrate (1.71 ml, 10 mmol) and titanium(IV) isopropoxide
 (1.5 ml, 5 mmol) are dissolved in methylene chloride (50 ml). Water (90
 .mu.l, 5 mmol) is added with stirring and the resultant mixture is heated
 to reflux for one hour. The mixture is cooled to room temperature.
 Thereafter,
 (5)6-methoxy-2-[[(4-methoxy3,5-dimethyl-2-pyridinyl)mrthyl]thiol-1H-benzim
 idazole (1.65 g, 5 mmol) and cumene hydroperoxide (80%, 1.5 g, 5.5 mmol)
 are added at room temperature. The solution is stirred at room temperature
 for 90 minutes. The final product provides
 (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]1H-be
 nzimidazoles.
 EXAMPLE 20
 Preparation of
 (-)-(5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-
 1H-benzimidazole Magnesium Salt
 To a nitrogen-purged flask containing 50 mL of methanol was added with
 stirring 0.11 g (4.5 mmol) of magnesium metal, followed by a catalytic
 amount (.about.0.5 mL) of methylene chloride. This mixture was heated to
 40.degree. C. for 5 hours, then removed from the heat an allowed to cool
 to ambient temperature. To the cloudy, stirring solution was added
 approximately 2 g of
 (-)-5(6)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-
 1H-benzimidazole. The flask was purged well with nitrogen, sealed and
 allowed to stir at ambient temperature overnight. Approximately 0.1 mL of
 water was then added to the reaction mixture and allowed to stir for 30
 minutes to precipitate inorganic magnesium salts. The mixture was then
 vacuum filtered, and the filtrate reduced to approximately 20% of the
 original volume under reduced pressure. To that resulting solution was
 added with stirring 100 mL of acetone. After approximately 5 minutes of
 stirring,. a precipitate began to form. The mixture was allowed to stir
 for an additional 30 minutes. The solids were isolated by vacuum
 filtration and washed with some fresh acetone. The solids were allowed to
 air dry to yield 640 mg of the desired product.
 EXAMPLE 21-29
 Preparation of
 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz
 imidazole from Mixtures of 5- and 6-methoxy Benzimidazoles
 Compositions which are formed in Examples 3-10 are subjected to the
 procedure set forth in Example 1. Pure 6-methoxy compounds were thereafter
 obtained from this procedure.
 EXAMPLE 30-33
 Preparation of
 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz
 imidazole from Mixtures of 5- and 6-methoxy Benzimidazoles
 Compositions which are formed in Examples 15-17 and 20 are subjected to the
 procedure set forth in Example 1. Pure salts of the 6-methoxy compounds
 were thereafter obtained from this procedure.
 EXAMPLE 34
 Determination of Percentage of Co-Crystallized 5- and
 6-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl-sulfinyl]-1H
 Benzimidazole Isomers
 Typically, a single Crystal X-Ray Diffraction was used to determine the
 percentage of 5- and
 6-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzi
 midazole isomers in an API. Without being bound to theory, it is believed
 that a crystalline material diffracts X-rays due to the constructive and
 destructive interference of the scatter of X-rays from the atoms of the
 molecule within the crystal lattice. The intensity and positions of the
 diffraction spots produced by the crystal is capable of generating
 structural information about the locations of the atoms in the molecule of
 a crystal.
 In this instance, a single crystal of the material to be examined is
 mounted at the end of a glass fiber. The crystal is aligned in the
 diffractometer in a specific orientation. The diffraction spots are
 measured, then the crystal is rotated to the next position. The above
 sequence is then repeated until thousands of individual diffraction spots
 are measured and recorded. The diffraction spots are then analyzed and the
 data phased to generate an electron density map from which a molecular
 structure of the molecule is uniquely determined. The X-ray diffraction
 data is generated using either a Nonius CAD4 diffractometer or a Nonius
 Kappa CCD diffractometer made commercially available by Nonius Corporation
 of Delft, Netherlands. The diffraction data generated for the various
 batches of omeprazole API tested shows the molecular structure of the drug
 present. It was determined from the data that the crystal lattice
 contained various degrees of disorder of the 6 and 5-methoxy isomers
 within the API. The two isomers were found to co-crystallize within a
 single crystal lattice. This co-crystallization within the single lattice
 is believed to cause a distortion of the six independent unit cell
 parameters in relation to the amount of each isomer present. The exact
 amount of 5-methoxy isomer present was determined by a least-squares
 minimization of the data. A linear regression analysis of the cell
 constants to the percentage of the 5-methoxy isomer present demonstrated
 good correlation coefficients.
 In this example, the compounds were found to contain predominantly two
 diastereomers, namely the S--S and R--R derivatives. Such proposed
 behavior was not expected, since the manner in which the compounds were
 synthesized is believed to be non-discriminatory towards selection of the
 S or R chiral plane with the corresponding S or R chiral center. Although
 not intending to be bound by theory, structural analysis reveals that the
 5- and 6-methoxy isomers crystallize through a center of inversion and are
 linked by hydrogen bonding from the amine hydrogens to the sulfoxide
 oxygens. The methoxy methyls are believed to be directed towards the
 center of the bridged complex. Again not being bound by theory,
 examination of the contact distances in the region where the other methoxy
 methyl may reside reveals that there may not be adequate space within the
 lattice for the other diastereomer (S--R and R--S) to co-exist. The oxygen
 atom of the methoxy is observed to sit only about 3.6 .ANG. from 4 other
 non-hydrogen atoms and 3.2 .ANG. from 2 hydrogen atoms of an adjoining
 molecule of omeprazole. Normal Van DerWaals contact distances are
 typically about 3.7 .ANG. for non-hydrogen atoms.

Enteric Coated Tablet
 A formulation employing an active ingredient is made according to the
 following recipe:
 g
 Core Material
 Active Ingredient 225
 Mannitol 1425
 Hydroxypropyl cellulose 60
 Microcrystalline cellulose 40
 Anhydrous lactose 80
 Sodium lauryl sulfate 5
 Dibasic sodium phosphate dihydrate 8
 Purified water 350
 Separating Layer
 Core material 300
 Hydroxypropyl cellulose 30
 Talc 51
 Magnesium stearate 4
 Water 600
 Enteric Coating Layer
 Pellets covered with separating layer 279
 Methacrylic acid copolymer 140
 Triethyl citrate 42
 Mono- and diglycerides 7
 Polysorbate 80 0.7
 Water 300
 Tablets
 Enteric coating layered pellets 352
 Microcrystalline cellulose 1,052
 Sodium Stearyl fumarate 3
 Sodium lauryl sulfate is dissolved in purified water to form a granulation
 liquid. The active ingredient along with the other dry ingredients used in
 making the core are dry mixed. The granulation liquid is added to the
 powder mixture and the resulting mass is kneeded and granulated to a
 proper consistency.
 The wet mass is forced through an extruder equipped with screens. The
 extrudate is spheronized in a spheronizing apparatus. The core material is
 dried in a fluid bed dryer and classified into a suitable particle range.
 The prepared core material is covered with a separating layer in a fluid
 bed apparatus with a hydroxypropyl methylcellulose solution containing
 talc and magnesium stearate.
 The enteric coating layer is sprayed onto the pellets covered with the
 separating layer from an aqueous dispersion of methacrylic acid copolymer,
 mono- and diglycerides, triethyl citrate, and polysorbate in a fluid bed
 apparatus.
 Enteric coating layered pellets, microcrystalline cellulose and sodium
 stearyl fumarate are mixed and compressed into tablets using a rotary
 tableting machine.

Tablet
 A tablet is formed from the following ingredients:
 Ingredient g
 active ingredient 400-430
 lactose, anhydrous 1,400-1,420
 polyvinylpyrrolodine 100
 sodium carbonate, anhydrous 15
 methyl cellulose 12
 distilled water 200
 magnesium stearate 30
 The active ingredient, lactose, polyvinylpyrrolidone, and sodium carbonate
 are homogenized and granulated by the addition of the methyl cellulose and
 distilled water. The wet mass is dried in a fluidized bed drier using an
 inlet air temperature of +50.degree. C. for 30 minutes. The dried mixture
 is then forced through a sieve with an aperture of 0.5 mm. After mixing
 with magnesium stearate, the granulate is tableted on a tableting machine
 using 6 mm punches. The tablet weight is 100 mg. The tablet may optionally
 be coated with the separating layer and/or enteric coating as described in
 Example 35.
 EXAMPLE37
 Capsule

Capsule
 A capsule containing 30 mg of the active ingredient is prepared from the
 following ingredients:
 Ingredient g
 active ingredient 300
 lactose 700
 microcrystalline cellulose 40
 hydroxypropyl cellulose, low-substituted 62
 disodium hydrogen phosphate 2
 purified water q.s.
 The active compound is mixed with the dry ingredients and granulated with a
 solution of disodium hydrogen phosphate. The wet mass is forced through an
 extruder and spheronized and dried in a fluidized bed drier. The resulting
 pellets are filled into capsules. Prior to being filled into capsules, the
 pellets may optionally be coated with the separating layer and/or enteric
 coating as described in Example 36.
 The examples and embodiments as set forth in the detailed description are
 for illustrative purposes only and do not limit the scope of the
 invention.