Note: Descriptions are shown in the official language in which they were submitted.
~ 24205-714E
1 338399
This application is a division of application Serial
No. 529,605 filed February 12, 1987.
This invention relates to a pharmaceutical composition
which comprises 2-[(2-pyridyl)methylsulphinyl]benzimidazole or a
derivative thereof (hereinafter sometimes referred to
collectively as "benzimidazole compounds"), which is useful as
an antiulcer agent. The composition is stabilized by incorpora-
tion of an effective amount of a basic inorganic salt stabilizing
agent, with basic inorganic salts of magnesium, calcium,
potassium and sodium being useful, the magnesium and calcium
salts being preferred.
Certain benzimidazole compounds are recently under
clinical study as gastric acid secretion inhibitors. They serve
as therapeutic agents for digestive ulcer. Their principal
pharmacological effect consists in gastric acid secretion
suppression based on (H + K )-ATPase inhibition and is more
potent and durable as compared with histamine H2 receptor
antagonists such as cimetidine and ranitidine. They also have
gastric mucosa protecting activity. Therefore, they have
attracted attention as next-generation potent therapeutic agents
for digestive ulcer.
- 2 - 1 338399
Those benzimidazole compounds which are described in
Japanese Unexamine~ Patent laid open Nos. 62275/77,
141783/79, 53406/~2, 135881/83, 192880/83 and 181277/84,
corresponding to U.S. Patent No. 4,045,563, U.S. Patent No.
4,255,431, European Patent P~lication No, 45,200, U.S. ~atent No.
No. 4,472,409, European Patent Publication No. 5,129 and
G.B. Patent Publication No. 2,134,523A, respectively,
among others are known to have antiulcer activity.
These compounds, however, are poor in stability. In
solid state, they are susceptible to heat, moisture and
light and, in aqueous solution or suspension, their stabil-
ity decreases with decreasing pH. In dosage forms, i.e.
tablets, powders, fine granules~ granules and capsules,
said compounds are apt to interact with other components
contained in said dosage forms and accordingly are in less
stable state as compared with the case where they occur
alone. Thus, the content decreases and the color changes
significantly in the manufacturing process of dosage form
and with the lapse of time. Microcrystalline cellulose,
polyvinylpyrrolidone (PVP), carboxymethylcellulose calcium,
- 3 - 1338399
polyethylene glycol 6000 and Pluronic F68 (polyoxyethylene-
polyoxypropylene copolymer), for instance are dosage form
components adversely affecting the stability of said com-
pounds. Furthermore, in the case of coated tablets and
coated granules among the above dosage forms, enteric coat-
ing bases such as cellulose acetate phthalate, hydroxy-
propylmethylcellulose acetate succinate and Eudragit (meth-
acrylic acid-acrylic acid copolymer) have poor compatibility
with said compounds and cause content decrease and color
change. Nevertheless, one or more of these components or
ingredients, which, as mentioned above, can produce adverse
effects on the stability of said compounds, are essential
in the manufacture of oral preparations and therefore dif-
ficulties are inevitably encountered in dosage form manu-
facture.
The prior art avoids the above-mentioned stability
problem by using said benzimidazole compounds in a salt
form, say in the form of a lithium, sodium, potassium,
magnesium, calcium or titanium salt [Japanese Unexamined
Patent laid open No. 167587/84 (European Patent Publication
No. 124,495A)]
However, the above prior art method requires, for the
stabilization of the benzimidazole compounds, a step of
converting said compounds to such a salt form as mentioned
above in advance.
In view of the above, the present inventors made in-
1 338399
vestigations in an attempt to stabilize pharmaceutical
preparations containing benzimidazole compounds and, as a
result, have completed the present invention.
Thus, the subject matter of this divisional
application relates to:
a stabilized pharmaceutical composition for the
inhibition of gastric acid secretion, comprising:
an effective amount of 2-[(2-
pyridyl)methylsulfinyl~-benzimidazole compound having a
gastric acid secretion inhibitory property or a
pharmaceutically acceptable salt thereof;
a basic inorganic salt stabilizing agent which is
present in an amount effective to stabilize the composition,
the benzimidazole compound or its salt being in contact with
the basic inorganic salt evenly; and
an enteric coating for the composition,
with the proviso that the 2-[~2-pyridyl)-
methylsulfinyl]benzimidazole compound is neither
2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]-
methylsuifinyl]benzimidazole nor 5-methoxy-2-[(4-methoxy-3,5-
dimethyl-2-pyridyl)methylsulfinyl]benzimidazole, and
with the further proviso that the basic inorganic
salt stabilizing agent is other than calcium and magnesium
salt when the 2-[(2-pyridyl)methylsulfinyl]benzimidazole
compound is a compound of formula (I) described hereinunder.
It should be noted that the expression "this
invention" or the like in this specification includes subject
matter of this divisional application as well as that of the
-- 4
24205-714E
- 1 338399
parent application and another divisional application.
Examples of the benzimidazole compounds having an
antiulcer activity which are to be used in the practice of the
invention include those compounds which are described in the
above-cited laid-open patent specifications, for instance and
are represented by the formula:
H~
l2
wherein R1 is hydrogen, alkyl, halogen, cyano, carboxy,
carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl,
- 4a -
24205-714E
- 5 ~ 1 338399
-
hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl, acyl,
carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio
or alkylsulfinyl, R2 is hydrogen, alkyl, acyl, carboalkoxy,
carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonyl-
methyl, alkoxycarbonylmethyl or alkylsulfonyl, R3 and R5are the same or different and each is hydrogen, alkyl,
alkoxy or alkoxyalkoxy,R4 is hydrogen, alkyl, alkoxy
which may optionally be fluorinated, or alkoxyalkoxy, and
m is an integer of 0 through 4.
The compounds of the formula(I) can be produced
by the methods described in the above-cited laid-open
patent specifications or modifications thereof.
In the following, brief mention is made of the sub-
stituents in those compounds which have the for-
lS mula (I) and are already known.
Referring to R in the above formula, Cl 7 alkylsmay be mentioned as the alkyl represented by R1; C1 4
alkoxys as the alkoxy moiety of the carboalkoxy; C1 4
alkoxys as the alkoxy moiety of the carboalkoxyalkyl
and Cl 4 alkyls as the alkyl moiety; C1 4 alkyls as the
alkyl moiety of the carbamoylalkyl; Cl 5 alkoxys as the
alkoxy; Cl 7 alkyls as the alkyl moiety of the hydroxy-
alkyl; Cl_4alkanoyls as the acyl; phenyl as the aryl; phenyl
as the aryl moiety of the aryloxy; Cl 6 alkyls as the
alkyl moiety of the alkylthio; and Cl 6 alkyls as the
alkyl moiety of the alkylsulfinyl.
Referring to R2, Cl 5 alkyls may be mentioned as
~ 24205-714E
~ - 6 - 1338399
the alkyl represented by R2; Cl 4alkanoyls as the acyl;
C1 4 alkoxys as the alkoxy moiety of the carboalkoxy;
Cl 4 alkyls as the alkyl moiety of the alkylcarbamoyl;
C1 4 alkyls as each of the alkyl moieties of the dialkyl-
carbamoyl; Cl 4 alkyls as the alkyl moiety of the alkyl-
carbonylmethyl; C1_4 alkoxys as the alkoxy moiety of the
alkoxycarbonylmethyl; and Cl 4 alkyls as the alkyl moiety
of the alkylsulfonyl.
Referrring to R3, R4 and RS, Cl 4 alkyls may be men-
tioned as the alkyl represented by any of them; Cl 8alkoxys as the alkoxy; and Cl 4 alkoxys as each of the alkoxy
moieties of the alkoxyalkoxy.
Referring to R , Cl 8 alkoxys may be mentioned as
the alkoxy, which may optionally be fluorinated.
Among those compounds of the above forumula
(I), (1) the compounds of which R1 is hydrogen, methoxy
or trifluoromethyl, R2 is hydrogen, R3 and RS are the
same or different and each is hydrogen or methyl, R4 is
fluorinated C2_s alkoxy and m is 1, (2) the compounds of
which R1 is hydrogen, fluorine, methoxy or trifluoro-
methyl, R2 is hydrogen, R3 is hydrogen or methyl, R4 is
C3-8 alkoxy, RS is hydrogen and m is 1, and (3) the
compounds of which Ri is hydrogen, fluorine, methoxy or
trifluoromethyl; R2 is hydrogen, R3 is Cl_g alkoxy, R4
is Cl 8 alkoxy wilich may be fluorinated, R5 is hydrogen
and m is 1 are novel.
Detailed mention is now made of the substituents
~ 24205-714E
~ ~ 7 ~ 1 338399
in such novel compounds.
Referring to R3, the lower alkyl represented thereby
is preferably Cl_8 lower alkoxy such as methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyl-
oxy, heptyloxy or octyloxy and more preferably C1 4 loweralkoxy.
Referring to R4, Cl 8 lower alkoxys may be mentioned
as the lower alkoxy, which may optionally be fluorinated,
and preferred examples are as mentioned above for R3. As
the fluorinated lower alkoxy, there may be mentioned, for
example, 2,2,2-trifluoroethoxy, 2,2,3,3,3-pentafluoro-
propoxy, l-(trifluoromethyl)-2,2,2-trifluoroethoxy, 2,2,3,3-
tetrafluoropropoxy, 2,2,3,3,4,4,4-heptafluorobutoxy and
2,2,3,3,4,4,5,5-octafluoropentoxy, and fluorinated C2 4
lower alkoxys are preferred.
The position of R1 is position 4 or position 5,
preferably position 5.
Some methods of producing the above novel compounds
[hereinafter referred to as "compounds of formula (I')"]
are described below.
Said compounds can be produced by subjecting a com-
pound of the formula
R~
(R m~ ~ ~ S - Cll~
R~
~ - 8 - 1338399
wherein Rl-R5 are as defined above, to oxidation.
The oxidizing agent to be used is, for example,
meta-chloroperbenzoic acid, peracetic acid, trifluoroper-
acetic acid, permaleic acid or the like peracid, sodium
bromite or sodium hypochlorite. Examples of the solvent
to be used in carrying out the reaction are halogenated
hydrocarbons such as chloroform and dichloromethane, ethers
such as tetrahydrofuran and dioxane, amides such as di-
methylformamide, and water. These solvents may be used
either singly or in admixture. Said oxidizing agent is
used preferably in an amount approximately equivalent or
slightly excessive relative to the compound (II). Thus,
said agent is used in an amount of about 1-3 equivalents,
more preferably about 1 to 1.5 equivalents. The reaction
is carried out at a temperature from about 0C (ice cool-
ing) to around the boiling point of the solvent used,
generally at a temperature from about 0C (ice cooling)
- to room temperature, preferably at a temperature of about
0C to 10C. The reaction time is generally about 0.1
to 24 hours, preferably about 0.1 to 4 hours.
The desired novel compounds (I') produced by the
above reaction can be isolated and purified by conven-
tional means such as recrystallization, c ~ n~tography and so on.
Said compounds may be converted to pharmacologically
acceptable salts by conventional means. As such salts,
there may be mentioned hydrochloride, hydrobromide, hydro-
iodide, phosphate, nitrate, sulfate, acetate and citrate,
~ 24205-714E
1 338399
among others.
The novel compounds (II) can be produced by reacting
a starting compound of the formula
( )m ~ ~ ~ SH (m)
R2
wherein Rl and R2 are as defined above, with a starting
compound of the formula
R~
R3~R~ (~r )
XCN 2
wherein R3-R5 are as defined above and X is a halogen
atom.
The halogen atom represented by X is, for example,
chlorine, bromine or iodine.
The reaction is carried out advantageously in the
presence of a base. As said base, there may be mentioned
alkali metal hydrides such as sodium hydride and potassium
hydride, alkali metals such as metallic sodium, sodium
alcoholates such as sodium methoxide and sodium ethoxide,
alkali metal carbonates such as potassium carbonate and
sodium carbonate, and organic amines such as triethylamine,
among others. As the solvent to be used in carrying out
the reaction, there may be mentioned, for example, alcohols
such as methanol and ethanol, and dimethylformamide. The
~ lo - 1 338399
base is used generaIly in an amount slightly excessive
relative to the equivalent amount but may also be used
in large excess. Thus, it is used in an amount of about
2-10 equivalents, preferably about 2-4 equivalents. The
S above reaction is carried out generally at a temperature
of about 0C to around the boiling point of the solvent
used, preferably at about 20C to 80C, for a period of
about 0.2-24 hours, preferably about 0.5-2 hours.
Some methods of producing the startlng compounds
(IV) are described below.
Among the compounds (IV), those compounds ~herein
R3 and R5 are the same or different and each is hy ~ gen or methyl
and R4 is fluorinated C2 5 alkoxy or C3 8 alkoxy can be
produced by the following process:
lS Process 1)
NO2 R~
R ~ R R4 OH (~1) R ~ R
O O
(V) (~)
R4 R4
CH3COCH2 N HOCH2 N
(vm) (IX)
1 338399
A nitro compound of the formula (V), wherein R3
and R5 are as defined above, is reacted with an alcohol de-
rivative of the formula R OH (VI) wherein R is fluori-
nated C2 5 alkyl or C3 8 alkyl, in the presence of a base to
give an alkoxy derivative of the formula (VII) wherein
R3, R4 and R5 are as defined above. The base to be used
in carrying out the reaction includes, among others, al-
kali metals such as lithium, sodium and potassium, alka-
li metal hydrides such as sodium hydride and potassium
hydride, alcoholates such as potassium t-butoxide and
sodium propoxide, alkali metal carbonates and hydrogen
carbonates such as potassium carbonate, lithium carbonate,
sodium carbonate, potassium hydrogen carbonate and sodium
hydrogen carbonate,
and alkali metal hydroxides such as
sodium hydroxide and potassium hydroxide. The alcohol
derivative to be submitted to the reaction includes, among
others, propanol, isopropanol, butanol, pentanol, hexanol,
2,2,2-trifluoroethanol, 2,2,3,3,3-pentafluoropropanol,
2,2,3,3-tetrafluoropropanol, 1-(trifluoromethyl)-2,2,2-
trifluoroethanol, 2,2,3,3,4,4,4-heptafluorobutanol and
2,2,3,3,4,4,5,5-octafluoropentanol. While R4 OH itself
may be used as a solvent in carrying out the reaction,
ethers such as tetrahydrofuran and dioxane, ketones such
as acetone and methyl ethyl ketone, acetonitrile, dimethyl-
fo~mi~ and hex ~ thylphosphoric acid triamide, for ins~noe, may
also be used as solvents. An appropriate reaction tem-
` - 12 - 1338399
perature may be selected within the range of about 0C
(ice cooling) to around the boiling point of the solvent
used. The reaction time is about 1-48 hours.
Heating (about 80-120C) of the thus-obtained com-
s pound (VII) with acetic anhydride alone or in the presence
of an inorganic acid such as sulfuric acid or perchloric
acid gives an 2-acetoxymethylpyridine derivative of the
formula (VIII) wherein R3, R4 and R5 are as defined
above. The reaction period is generally about 0.1-10
hours.
The subsequent alkaline hydrolysis of the compound
(VIII) gives a 2-hydroxymethylpyridine derivative of the
formula (IX). Sodium hydroxide, potassium hydroxide,
potassium carbonate and sodium carbonate, for instance,
are usable as alkalis, and methanol, ethanol and water,
among others, are usable as solvents. The reaction is
generally conducted at about 20-60C for about 0.1-2
hours.
The compound (IX) is further halogenated with a
chlorinating agent such as thionyl chloride to give a
2-halomethylpyridine derivative of the formula (IV)
wherein R3, R4 and R5 are as defined above and X is
chlorine, bromine or iodine. Usable as solvents are,
for example, chloroform, dichloromethane and tetrachloro-
ethane. The reaction is generally carried out at about20-80C for about 0.1-2 hours.
The compound (IV) thus produced occurs in the form
(_!
~ -13- 1 338399
of a salt of hydrohalogenic acid corresponding to the
halogenating agent used and it is generally preferable to
subject said compound to reaction with the compound (III)
immediately.
Among the compounds (V), those compounds wherein R3
is Cl 8 lower alkoxy, R4 is alkoxy which may optionally
be fluorinated, and R5 is hydrogen can be produced by the
following process:
Process 2)
0 0 0
~XCN ~ C~ R
(x) (~) ~ (~)
~ ~I
R~ ~/ X
~CN3 R~ OH ~C8
( X m ) \~ R~
~!XR
N CH3 ~ h~ R3
~N~CH 20COCH3
(xv) (xv[)
R~
~CH OH
-(~) (x v~)
- 14 - 1338399
Thus, maltol (X) is reacted with a alkyl halide of
the formula R3 X in the presence of silver oxide, for
instance, to give a compound of the formula (XI). Reaction
of lXI) with aqueous ammon~ia gives a pyridone derivative
S of ~e fonmula (XII). Direct alkylation of the compound (XII)
with an alkyl halide, or halogenation of (XII) with a
halogenating agent such as phosphorus oxychloride follow-
ed by reaction of the resultant halo derivative (XIV) with
a lower alcohol of the formula R4 OH in the presence of
a base gives a compound of the formula (XIII). The com-
pound (XIII) can be converted to the compound (IV) by
direct halogenation with N-bromosuccinimide or chlorine,
for instance. The compound (XIII) may also be converted
to the compound (IV) by oxidizing the same with an oxi-
dizing agent such as m-chloroperbenzoic acid, reacting
the resulting compound (XV) with acetic anhydride, hydro-
lyzing the resulting comppund (XVI) and halogenating the
resulting compound (XVII) with a halogenating agent such
as thionyl chloride.
The alkyl halide to be used in the production of the
compound (XI) includes, among others, methyl iodide,
ethyl iodide, propyl iodide, isopropyl iodide, butyl
iodide, pentyl iodide and hexyl iodide, and the alkyl
halide to be used in the production of the compound
(XIII) further includes, in addition to those mentioned
above for use in the production of the compounds (XI),
2,2,2-trifluoroethyl iodide, 2,2,3,3,3-pentafluoropropyl
- 15 - 1 3 38399
iodide, 2,2,3,3-tetrafluoropropyl iodide, 1-(trifluoro-
methyl)-2,2,2-trifluoroethyl iodide, 2,2,3,3,4,4,4-hepta-
fluorobutyl iodide and 2,2,3,3,4,4,5,5-octafluoropentyl
iodide, for instance. Such alkyl iodides are used in an
amount of about l-I0 equivalents. Silver oxide, potas-
sium carbonate, sodium carbonate or the like is used as
a deacidifying agent and dimethylformamide, dimethylacet-
amide or the like is used as a solvent. The reaction is
generally carried out at room temperature.
The halogenating agent to be used in the production
of the compound (XIV) includes, among others, phosphorus
oxychloride, phosphorus pentoxide and phosphorus tribro-
mide and is used in an amount of 1 equivalent to a large
excess. The reaction is carried out at a temperature of
about 50-150C. The alcohol to be used for the conver-
sion of compound (XIV) to compound (XIII) includes metha-
nol and ethanol and further those alcohol derivaitves
mentioned for use in process 1) and is used in an amount
of 1 equivalent to a large excess, and the base includes
those sodium alcoholates and potassium alcoholates which
correspong to the respective alcohols as well as potas-
sium t-butoxide, sodium hydride and so forth. An appro-
priate reaction temperature may be selected within the
range of room temperature to the boiling point of the
solvent used.
For direct bromination of the compound (XIII) with
N-bromosuccinimide, the reaction is preferably carried
- 16 - 1 33 8399
out under light irradiation, and carbon tetrachloride,
chloroform, tetrachloroethane or the like is used as a
solvent.
The oxidizing agent to be used for the conversion of
compound (XIII) to compound (XV) includes, among others,
peracids such as meta-chloroperbenzoic acid, peracetic
acid, trifluoroperacetic acid and permaleic acid as well
as hydrogen peroxide. Usable as solvents for the reaction
are halogenated hydrocarbons such as chloroform and di-
chloromethane, ethers such as tetrahydrofuran and dioxane,amides such as dimethylformamide, acetic acid and water,
for instance,.and these can be used either singly or in
admixture. Said oxidizing agent is preferably used in an
amount of about 1 equivalent to an excess relative to the
compound (XIII), more preferably about 1-10 equivalents.
The reaction is carried out at a temperature of about 0C
(ice cooling) to around the boiling point of the solvent
used generally for a period of about 0.1-24 hours, prefer-
ably for about 0.1-4 hours.
The conversion of compound (XV) to compound (XVI) is
effected by heating (at about 80-120C) the compound (XV)
with acetic anhydride alone or in the presence of an in-
organic acid such as sulfuric acid ~r per*~oric acid and so on.
The reaction period is generally 0.1-10 hours.
The alkali to be used in the alkaline hydrolysis of
compound (XVI) to compound (XVII) includes,-among others,
sodium hydroxide, potassium hydroxide, potassium carbonate
- 17 - 1 338399
and sodium carbonate. Methanol, ethanol and water, for
instance, may be mentioned as usable solvents. The re-
action is generally carried out at a temperature of about
20-60C for a period of about 0.1-2 hours.
For the production of compound (IV) from compound
(XVII), a chlorinating agent such as thionyl chloride or
an organic sulfonic or organic phosphoric acid chloride
such as methanesulfonyl chloride, p-toluenesulfonyl
chloride or diphenylphosphoryl chloride is used. When
a chlorinating agent such as thionyl chloride is used,
it is used in an amount of 1 equivalent to a large excess
relative to the compound (XVII) and a solvent such as
chloroform, dichloromethane or tetrachloroethane is used,
and the reaction is generally carried out at a temperature
lS Of about 20-80C for a period of about 0.1-2 hours. When
an organic sulfonic or organic phosphoric acid chloride
is used, it is used in an amount of l equivalent to a
slight excess relative to the compound (XVII) and the re-
action is generally carried out in the presence of a base.
As usable bases, there may be mentioned organic bases
such as triethylamine and tributylamine and inorganic
bases such as sodium carbonate, potassium carbonate and
sodium hydrogen carbonate. The base is used in an amount
of 1 equivalent to a slight excess. As usable solvents,
there may be mentioned, for example, chloroform, dichloro-
methane, carbon tetrachloride and acetonitrile. An appro-
priate reaction temperature and an appropriate reaction
~ - 18 - 1 338399
~ 24205-714E
can be selected within the ranges of about 0C (ice cooling) to
around the boiling point and several minutes to several hours,
respectively.
The above-mentioned novel benzimidazole compounds have
excellent gastric antisecretory activity, gastric mucosa-
protecting activity and antiulcer activity but have low toxicity,
so that they can be used in the treatment of digestive ulcers in
mammals (e.g. mouse, rat, rabbit, dog, cat, human).
The basic inorganic stabilizing agents which are used
in accordance with the invention, are now described.
Especially useful basic inorganic salt stabilizing
agents are basic inorganic salts of magnesium and calcium.
Those basic inorganic magnesium compounds include,
among others, heavy magnesium carbonate, magnesium carbonate,
magnesium oxide, magnesium hydroxide, magnesium metasilicate
aluminate, magnesium silicate aluminate, magnesium silicate,
magnesium aluminate, synthetic hydrotalcite
[Mg6A12(OH)16 CO3 4H2O] and aluminum magnesium hydroxide
[2.5MgO A12O3-xH2O] and those basic inorganic calcium compounds
include among others, (precipitated) calcium carbonate and
calcium hydroxide. Other basic inorganic salts useful as
stabilizing agents include sodium and potassium salts such as
potassium carbonate, sodium carbonate and sodium hydrogen
carbonate, a-s well as aluminum basic salts such as aluminum
silicate. It is only required of such basic inorganic salts to
show basicity (pH of not less than 7) when they are in the form
of a 1-% aqueous solution or suspension.
19 - 1 3383q9
24205-714E
Those basic inorganic compounds may be used either
singly or in combination of two or more species in an amount
which may vary depending on the kinds thereof but generally lies
within the range of about 0.3-20 parts by weight, preferably
about 0.6-7 parts by weight, per part by weight of the
benzimidazole compounds.
The composition of the invention may further contain
such additives as vehicles (e.g. lactose,- corn starch, light
silicic anhydride, microcrystalline cellulose, sucrose), binders
(e.g. a-form starch, methylcellulose, carboxymethylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl-
pyrrolidone), disintegrating agents (e.g. carboxymethylcellulose
calcium, starch, low substituted hydroxypropylcellulose),
surfactants [e.g. Tween 80 (Kao-Atlas: polyoxyethylene sorbitan
fatty acid ester), Pluronic F68 (Asahi Denka: polyoxyethylene-
polyoxypropylene block copolymer], antioxidants (e.g. L-cysteine,
sodium sulfite, sodium ascorbate), lubricants (e.g. magnesium
stearate, talc), etc.
The composition of the invention is prepared by homo-
geneously aAm;~;ng the above benzimidazole compound, the basicinorganic stabilizing agent t and the above additives.
The particle sizes of the benzimidazole compound and
the inorganic compound are not especially critical in a condition
that they can be homogeneously admixed. For example, preferable
particle size is about less than 100 ~m, more preferably one is
about less than 20 ~m.
*
Trade-mark
1 3 3 8 3 9 924205-714E
The moisture amount in the composition is preferably
about 6 - 60%, more preferably about 20 - 40~ as equili~rium
relative humidity (E.R.H.~. The method~of admixing is not
critical as far as the benzimidazole compound can finally be
made in even contact with the basic i~organic stabilizing agent.
Thus, for example* the additives may be admixed with a mixture
of the benzimidazole compound and the basic inorganic stabilizing
agent as prepared by preliminary a~ g, or the b-asic inorganic
- stabilizing agent may be added to a mixture of the benzimidazole
compound and the additives as prepared by prel;min~ry admixing.
The mixture can be made up into dosage forms suited
for oral administration, such as tablets, capsules, powders,
granules and fine granules, by per se known means.
Tablets, granules and fine granules are then coated by
a per se known method for the purpose providing enteric property,
optionally as well as for the purpose of masking the taste or
providing sustained release property. Usable as coating agents
are, for example, hydroxypropylmethylcellulose, ethylcellulose,
hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene
glycol, polyoxyethylene sorbitan fatty acid ester (e.g. Tween
80), polyoxyethylene-polyoxypropylene block copolymer (e.g.
*
Pluronic F68), cellulose acetate phthalate~, hydroxypropylmethyl-
cellulose phthalate, hydroxymethylcellulose acetate succinate and
methacrylic acid-acrylic acid copolymer (e.g. Eudragit (Rohm,
West Germany)). ~Pigments such as titanium oxide and ferric oxide
may be employed together.
- 21 - 1 338 399
24205-714E
Tablets, granules, powders, fine granules and capsules
can be produced by a conventional method~(e.g. the method
described in the 10th edition of the Japanese Pharmacopeia under
General Rules for Preparations). Thus, for example, tablets
are produced by adding the basic inorganic stabilizing agent to
a mixture of the benzimidazole compound, vehicle and disintegrant,
mixing, adding a binder granulating the mixture, adding a
lubricant etc. and tableting the resultant granular composition.
Granules are produced by extrusion in approximately the same
manner as in the production of tablets or by coating nonpareils,
which contain sucrose and corn starch, with a mixture of
benzimidazole compound, a basic inorganic stabilizing agent, and
additives (e.g.~, sucrose, corn starch, crystalline cellulose,
hydroxypropylcellulose, methylcellulose, hydroxypropylmethyl-
cellulose, polyvinylpyrrolidone).
1 338399
- 22 -
Capsules are produced by mere mixing and filling. The
dosage forms thus obtained show excellent stability with
slight changes in appearance and little decreases in con-
tent even after storage for a long period of time.
The pharmaceutical composition of the pres-
ent invention as obtained in the above manner exhibits
excellent gastric antisecretory, gastric mucosa-protecting
and antiulcer activities and has low toxicity and there-
fore can be used in the treatment of digestive ulcers
in mammals (e.g. mouse, rat, rabbit, dog, cat, pig,
human).
The pharmaceutical composition of the in-
vention can be orally administered for the treatment of
digestive ulcers in m~mm~l S in admixture with pharma-
lS cologically acceptable carriers, vehicles, diluents andso forth and in the form of capsules, tablets, granules
and some other dosage forms, as ~entioned hereinabove.
The dose as the benzimidazole compound lies within the
range of about 0.01 mg to 30 mg/kg/day, preferably about
0.1 mg to 3- mg/kg/day.
The following reference examples and working examples
as well as the experimental examples ~scrihP~ later herein illus-
; trate the present invention in more detail but are by no
25 means limitative of the present invention.
Reference Example 1
A mixture of 2,3-dimethyl-4-nitropyridine-1-oxide
- 23 - 1338399
(2.0 g), methyl ethyl ketone (30 ml), 2,2,3,3,3-penta-
fluoropropanol (3.05 ml), anhydrous potassium carbonate
(3.29 g) and hexamethylphospl~oric acid trlamide (2.07 g) w~s heated
at 70-80C with stirring for 4.5 days. Then, the insol-
uble matter was filtered off and the filtrate was concen-
trated. Water was added to the residue and the mixture
was extracted with ethyl acetate. The extract layer was
dried over magnesium sulfate, then the solvent was distil-
led off, and the residue was applied to a silica gel col-
umn (50 g). Elution with chloroform-methanol (10:1) and
recrystallization from ethyl acetate-hexane gave 2.4 g of
2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-
oxide as colorless needles. Melting point 148-149C.
The following compounds (VII) were produced from the
corresponding compounds (V) in the same manner as above.
Compounds (VII)
R3 R R4 Melting point (C)
CH3 H OCH2CF3 131.0-131.5
20 Note 1) H H OCH2CH2CH3 Oil
Note 2) CH3 H OCH2CH2CH3 Oil
Note 1): NMR spectrum (CDC13) ~: 1.01 (3H, t, J =
7 Hz), 1.81 (2H, m), 2.50 (3H, s), 3.93 (2H, t,
J = 7 Hz), 6.50-6.80 (2H, m), 8.10 (lH, d, J = 7
Hz)
Note 2): NMR spectrum (CDC13) ~: 1.07 (3H, t, J =
7.5 Hz), 1.65-2.02 (2H, m), 2.21 (3H, s), 2.52
(3H, s), 3.99 (2H, t, J = 6 Hz), 6.68 (lH, d, J =
- 24 - 1338399
6 Hz), 8.15 (lH, d, J = 6 Hz)
Reference Example 2
Concentrated sulfuric acid (2 drops) was added to a
solution of 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)-
pyridine-l-oxide (2.5 g) in acetic anhydride (8 ml) and
the mixture was stirred at 110C for 2 hours and then con-
cen-trated. The residue was dissolved in methanol (30 ml),
2 N aqueous sodium hydroxide (20 ml) was added, and the
mixture was stirred at room temperature for 2 hours. After
concentration, water was added to the resïdue and the mix-
ture was extracted with ethyl acetate. The extract was
dried over magnesium sulfate, the solvent was then distil-
led off, and the residue was applied to a silica gel (50 g)
column. Elution with chloroform-methanol (10:1) and re-
crystallization from isopropyl ether gave 1.6 g of 2-
hydroxymethyl-3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-
pyridine as a brown oil.
NMR spectrum (CDC13) ~: 2.07 (3H, s), 4.28 (lH, brs),
4.49 (2H, t, J = 12 Hz), 4.67 (2H, s), 6.69 (lH, d,
J = 5 Hz), 8.34 (lH, d, J = 5 Hz)
The following compounds (IX) were produced from the
corresponding compounds (VII) in the same manner as men-
tioned above.
Compounds (IX)
; 25 R3 R5 R4 Melting point (C)
CH3 H OCH2CF3 93.5-94.0
Note 1) H H OCH2CH2CH3 Oil
- 25 - 1 338 39~
Note 2) CH3 H OCH2CH2CH3 Oil
Note 1) NMR spectrum (CDC13) ~: 1.0 (3H, t, J = 7.5
Hz), 1.79 (2H, m), 3.92 (2H, t, J = 6 Hz), 4.51-
4.90 (lH, br), 4.68 (2H, s), 6.68 (lH, dd, J = 2
and 6 Hz), 6.80 ~lH, d, J = 2 Hz), 8.28 (lH, d,
J = 6 Hz)
Note 2) NMR spectrum (CDC13) o: 1.03 (3H, t, J = 7.5
Hz), 1.82 (2H, m), 2.02 (3H, s), 3.95 (2H, t, J =
6 Hz), 4.62 (2H, s), 5.20 (lH, brd, s), 6.68 (lH,
d, J = 6 Hz), 8.25 tlH, d, J = 6 Hz)
Reference Example 3
Thionyl chloride (0.2 ml) was added to a solution of
2-hydroxymethyl-3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-
pyridine (350 mg) in chloroform (10 ml) and the mixture
was refluxed for 30 minutes and then concentrated. The
residue was dissolved in methanol (5 ml) and the solution
was added to a mixture of 2-mercaptobenzimidazole (200 mg),
28~ sodium methoxide solution (1 ml) and methanol (6 ml).
The resultant mixture was refluxed for 30 minutes. The
methanol was distilled off, water was added to the residue,
and the mixture was extracted with ethyl acetate. The
extract was washed with dilute sodium hydroxide solution
and dried over magnesium sulfate. The solvent was then
distilled off, and the residue was applied to a silica gel
(20 g) column. Elution with ethyl acetate-hexane (2:1)
and recrystallization from ethyl acetate-hexane gave 370
mg of 2-[[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]-
- 26 - 1 3 38 399
methylthio]benzimidazole hemihydrate as colorless
plates. Melting point 145-146C.
The following compounds (II) were produced by react-
ing the compound (III) with the corresponding compound
S (IV) in the same manner as mentioned above.
Compounds (II)
R1 R2 R4Melting point (C)
H H CH3 H OCH2CF3 149-150
H H H H OCH2CH2CH384-86
Note) H H C 3 2 2 3 Oil
Note) NMR spectrum (CDC13) o: 0.98 (3H, t, J = 7.5
Hz), 1.54-1.92 (2H, m), 2.15 (3H, s), 3.80 (2H,
t, J = 6 Hz), 4.43 (2H, s), 6.55 (lH, d, J = 6
Hz), 7.09 (2H, m), 7.50 (2H, m), 8.21 (lH, d, J =
6 Hz)
Reference Example 4
A solution of m-chloroperbenzoic acid (1.3 g) in
chloroform (15 ml) was added dropwis-e to a solution of
2-~[3-methyl-4-(2~2~3~3~3-pentafuloropropoxy)-2-pyridyl]-
methylthio]benzimidazole(2.2 g) in chloroform (20 ml) with
ice cooling over 30 minutes and, then, the reaction mix-
ture was washed with saturated aqueous sodium hydrogen
carbonate solution, dried over magnesium sulfate and con-
centrated. The concentrate was applied to a silica gel
(50 g) column. Elution with ethyl acetate and recrystal-
lization from acetone-isopropyl ether gave 1.78 g of 2-~[3-
- 27 _ 1 3 38 399
methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]methyl-
sulfinyl]benzimidazole [hereinafter sometimes referred to
as compound (A)] as pale yellow prisms. Melting point
161-163~C (decomposition).
The following compounds (I) [hereinafter sometimes
referred to as compound (B), compound (C) and compound (D),
respectively] were produced in the same manner from the
corresponding compounds (II).
Compounds (I)
R1 R2 R3 R5 R4 Melting point (C)
(B) H H CH3 H OCH2CF3 178-182 (decomp.)
(C) H Hr H H OCH2CH2CH3 123-125 (decomp.)
(D~ H H CH3 H OCH2CH2CH3 81-83
lS Example 1
Of the components given below, the compound (A),
magnesium hydroxide, L-cysteine, corn starch and lactose
were mixed together, then microcrystalline cellulose,
light silicic anhydride and magnesium stearate, each in
half the intended amount, were added. After sufficient
admixing, the mixture was compression-molded on a dry
granulator (roller compactor; Freund, Japan. The compressed
mass was ground in a mortar, the resultant granular mass
was passed through a round sieve (16 mesh). The remain-
ing portions of microcrystalline cellulose, light silicicanhydride and magnesium stearate were added to the
sieved mass and, after admixing, the whole mixture was
- 28 - 1338399
made up into tablets each weighing 250 mg on a rotary
tableting machine (Kikusui Seisakusho, Japan).
Composition per tablet:
Compound (A) 50 mg
Magnesium hydroxide 30 mg
L-Cysteine 20 mg
Corn starch 20 mg
Lactose 65.2 mg
Microcrystalline cellulose 60 mg
Light silicic anhydride 1.8 mg
Magnesium stearate 3.0 mg
Total 250.0 mg
Example 2
Tablets were produced in the same manner as in Ex-
ample 1 except that omeprazole (Note) was used instead
of the compound (A).
Note: 5-Methoxy-2-1(4-methoxy-3,5-dimethyl-2-
pyridyl)meth~lsulfinyl]benzimidazole
Example 3
Of the components given below, the compound (B),
precipitated calcium carbonate, corn starch, lactose and
hydroxypropylcellulose were mixed together, water was
added, and the mixture was kneaded, then dried in
vaCuum at 40C for 16 hours, ground in a mortar and passed
through a 16-mesh sieve to give granules. To this
was added magnesium stearate and the resultant mixture
was made up into tablets each weighing 200 mg on a rotary
: tableting machine (Kikusui Seisakusho,Japan).
- 29 - 1338399
Composition per tablet:
Compound (B) 30 mg
Precipitated calcium carbonate 50 mg
Corn starch 40 mg
Lactose 73.4 mg
Hydroxypropylcellulose 6 mg
Magnesium stearate 0.6 mg
Water (0.05 ml)
Total ~ 200.0 mg
Example 4
Tablets were produced in the same manner as in Ex-
ample 3 except that timoprazole (Note) was used instead
of the compound (B).
Note: 2-[(2-Pyridyl)methylsulfinyl~benzimidazole
Example 5
The ingredients given below were mixed well in the
porportions given below, water was added, and the mixture
was kneaded and granulated in an extruder granulator
(Kikusui Seis~kusho;screen size 1.0 mm ~). The
granules were immediately converted to spherical form
in a spheronizer (Fuji Powder~s Marumerizer, Japan; 1,000
rpm). The spherical granules were then dried under vacuum
at 40~C for 16 hours and passed through round sieves to
give 12- to 42-mesh granules.
Composition per 200 mg of granules
Compound (B) 30 mg
Heavy magnesium carbonate 20 mg
- 30 - 1338399
Corn starch 80 mg
Microcrystalline cellulose 20 mg
Carboxymethylcellulose calcium 10 mg
Hydroxypropylcellulose 10 mg
Pluronic F68 4 mg
Lactose 26 mg
Water (0.1 ml)
Total 200 mg
Example 6
Granules were produced in the same manner as in
Example 5 except that the compound (D) was used instead
of the compound (B).
Example 7
Enteric granules were produced by coating the gran-
ules obtained in Example 3 with an enteric coating com-
position specified below using a fluidized bed granulator
(Okawara, Japan) under conditions such that the inlet air
temperature was 50C and the granule temperature was 40C.
No. 1 hard capsules were filled with the enteric granules
thus obtained in an amount of 260 mg per capsule using a
capsule filling machine (Parke-Davis, U.S.A.).
Enteric coating composition: .
Eudragit L-30D 138 mg (solids 41.4 mg)
Talc 4.1 mg
25 Polyethylene glycol 6000 12.4 mg
; Tween 80 2.1 mg
Water 276 ~1
- 31 _1 338 399
Composition of enteric granules:
Granules of Example 5 200 mg
Enteric coat 60 mg
Total 260 mg
5 Composition per capsule:
Enteric granules 260 mg
No. 1 hard capsule 76 mg
Total 336 mg
Example 8
Of the components given below, the compound (B),
magunesium carbonate, socrose, corn starch and crystalline
cellulose were thoroughly mixed together to obtain dusting
powder.
Nonpareils were put on a centrifugal fluidized coating-
granulatar (CF-360 Freund, Japan) and then coated with the
dusting powder as described above, while spraying
hydroxypropylcellulose solution [4% ~w/w)], to give
spherical granules. The spherical granules were dried in
vacuum at 40C for 16 hours and then passed through round
sieves to give 12 to 32-mesh granules.
Composition per 190 mq of granules:
: Nonpareil 75 mg
Compound (B) 15 mg
Magnesium carbonate 15 mg
Sucrose 29 mg
; Corn starch 27 mg
Crystalline cellulose 27 mg
- 32 - 1338399
Hydroxypropylcellulose 2 mg
[Hydroxypropoxy group content: 53.4-77.5%]
Water (0.05 ml)
Total 190 mg
Example 9
Enteric granules were produced by coating the granules
obtained in Example 8 with an enteric coatig composition
specified below usig a fluidized bed granulator (Okawara,
Japan) under conditions such that inlet air temperature was
50C and the granule temperature was 40C. No. 2 hard
capsules were filled with the enteric granules thus obtained
in an amount of 240mg per capsule using a capsule filling
. machine (Parke-Davis, USA).
Enteric coating composition:
Eudragit L-30D104.7 mg (solids 31.4 mg)
Talc 9.6 mg
Polyethylene glycol 6000 3.2 mg
Tween 80 1.6 mg
Titanium oxide 4.2 mg
Water (220 ~1)
Composition of enteric granules;
Granules of Example 8190 mg
Enteric coat 50 mg
Total 240 mg
Composition per capsule;
Enteric granules 240 mg
No. 2 hard capsule 65 mg
: Total 305 mg
~ 24205-714E
- 33 _ 1 338 399
Experimental Example 1
Granules were produced by the method of Example 5
and, after storage at 50C and 75% RH for 1 week, were
observed for changes in appearance. Granules were also
produced in the same manner except that lactose was used
instead of heavy magnesium carbonate or that one of other
additives specificed below in Table 1.
Table 1
Changes in apperance
Additive after 1 week at 50C
and 75% R~
Heavy magnesium carbonate
Magnesium oxide
Magnesium metasilicate aluminate
Synthetic hydrotalcite
Aluminum magnesium hydroxide
Magnesium silicate
Precipitated calcium carbonate
~ ~ - 24205-714E
- 34 - 1338399
Magnesium hydroxide
Sodium carbonate + (to.yellow)
Potassium carbonate + (to.yellow)
Sodium hydrogen carbonate+ (to yellow)
Magnesium chloride ++ (to violet)
Magnesium sulfate ++ (to violet)
Calcium chloride ++ (to violet)
Aluminum silicate + (to violet)
No additive (lactose)++ (to violet)
Notes: - : No changes in
+ : Moderately
++ : Severely
As a result, no substantial changes in appearance
were noted for the compositions supplemented with the
additives of the invention.
Experimental Example 2
Granules were produced in the same manner as in Example
5 except that the compound (A), the compound (C), the com-
pound (D), omeprazole or timoprazole was used instead ofthe compound (B). After storage at 50C and 75% RH for
1 week, they were observed for changes in appearance. As a
control to each composition, granules were also produced
in the same manner except that lactose was used instead of
heavy magnesium carbonate and stored under the same condi-
tions.
_ 35 - I 338 399
Changes in appear-
Compound Additive ance after 1 week
at 50C and 75~ RH
Compound (A) Invention: Heavy magnesium
carbonate
Control: Lactose . ++
Omeprazole Invention: Heavy magnesium
carbonate
Control: Lactose ++
Timoprazole Invention: Heavy magnesium
carbonate
Control: Lactose ++
Compound (C) Invention: Heavy magnesium
carbonate
Control: Lactose ++
Compound (D) Invention: Heavy magnesium
carbonate
Control: Lactose ++
Notes: - : No changes
++ : Severely
As is evident from the above results, the pharma-
ceutical compositions of the invention were all
stable whether the active ingredient was the compound (A),
omeprazole, timoprazole, the compound (C) or the compound
(D).
Experimental Example 3
Pharmaceutical compositions were produced in the same
manner as in Examples 3 and 5 except that
different basic inorganic Mg or Ca salts were used or that
lactose was used as a cont~l, and Example 6. After strage at 50C and
~ 36 _ 1 338399
75~ RH for 1 week or at 40C for 6 months, the compositions
were observed for changes in appearance and for active in-
gredient content (residual percentage).
- 37 - 1 338399
ul cn cn C~ G~
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Z a~ Z C~ Z 0~n~ ~ Z a~ Z a~ Z a~ a
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I ~ ~ ~ JJ 1r. ~ J~ J ~ ~ I
r , nJ , ,~ ~ n3 ~ ,1 r
r--l r1 ~ r i; r ~ rc~ Q) r ~ ~ ~a
nJ .~ ~ C ~ ~na3S~ ~ C ~ r'' n3 a~ :~
E ~ ~a S J L GJ ~ L ~ nJ
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- 38 - 1 338 399
The above results clea~ly indicate that the composi-
tions of the invention show no changes in appear-
ance at all and are stable in terms of the active ingredi-
ent content.
