JPH0338247B2 - - Google Patents

Description

[Detailed description of the invention]

Industrial Application Field The present invention relates to a free form of acid-labile 2-[(2-pyridyl)methylsulfinyl]benzimidazole or its derivatives (hereinafter referred to as 2-[(2- pyridyl)methylsulfinyl]
It is sometimes abbreviated as a benzimidazole compound or simply a benzimidazole compound. )
The present invention relates to a stabilized enteric-coated anti-ulcer solid composition (hereinafter sometimes simply referred to as a composition) comprising a basic inorganic salt of magnesium and/or calcium. BACKGROUND OF THE INVENTION Benzimidazole compounds have recently been clinically studied as gastric acid secretion inhibitors. The pharmacological effect of this compound is that it is a therapeutic agent for peptic ulcers whose main action is to suppress gastric acid secretion based on the (H ⁺ + K ⁺ )-ATPase inhibitory effect, and it is more effective than histamine _H2 receptor antagonists such as cimetidine and ranitidine. Its action is strong and lasts for a long time, and it also has gastric mucosal protective effects, so it is attracting attention as a next-generation powerful peptic ulcer treatment. Examples of benzimidazole compounds having anti-ulcer effects include, for example, JP-A-52-62275;
JP-A-54-141783, JP-A-57-53406, JP-A-58-135881, JP-A-58-192880
Compounds described in JP-A-59-181277 and the like are known. However, the stability of these compounds is poor; in a solid state, they are unstable to temperature, humidity, and light, and in an aqueous solution or suspension, the lower the pH, the more unstable they are. On the other hand, the stability of formulations, such as tablets, powders, fine granules, granules, and capsules, is unstable due to stronger interactions with other ingredients in the formulation than with the compound alone, and the The content decreases day by day and the color changes significantly. Examples of formulation components that adversely affect stability include microcrystalline cellulose, polyvinylpyrrolidone (PVP), calcium carboxymethylcellulose, polyethylene glycol 6000, and Pluronic F68 (polyoxyethylene-polyoxypropylene copolymer). Furthermore, when coating tablets and granules among these preparations, for example, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate, succinate, Eudragit (methacrylic acid/acrylic acid copolymer), etc. Poor compatibility with soluble bases,
This results in content loss and color change. However, in the production of oral preparations, although it is essential to mix one or more of these components, the stability is adversely affected as described above, making it difficult to formulate the preparation. In order to eliminate these instabilities, conventionally,
A benzimidazole compound converted into a salt of lithium, sodium, potassium, magnesium, calcium, titanium, etc. was used. (Tokukai Akira
59-167587) Problems to be Solved by the Invention However, according to the above method, in order to stabilize the benzimidazole compound, the step of converting it into a salt as described above was necessary. Means for Solving the Problems In view of the above circumstances, the present inventors investigated the stabilization of benzimidazole compound-containing preparations, and as a result, completed the present invention. That is, the present invention provides an acid-labile 2-[(2-pyridyl)methylsulfinyl]benzimidazole compound having an anti-ulcer effect, in which a basic inorganic salt of magnesium and/or calcium is added as a stabilizer. A stabilized enteric-coated anti-ulcer solid composition formed by uniform contact. The benzimidazole compound having an anti-ulcer effect used in the present invention is a compound described in the above-mentioned publications, etc., and is represented by the following general formula (). [Wherein, R ¹ is hydrogen, alkyl, halogen, cyano, carboxy, carbalkoxy, carbalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl ,
aryloxy, alkylthio or alkylsulfinyl, ^R2 is hydrogen, alkyl, acyl,
Carbalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl,
alkylsulfonyl, R ³ and R ⁵ are the same or different and hydrogen, alkyl, alkoxy or alkoxyalkoxy; R ⁴ is hydrogen, alkyl, optionally fluorinated alkoxy or alkoxyalkoxy; m is 0 to 4; Indicate each integer. ) The compound of general formula () can be produced by the method described in the above-mentioned publication or a method analogous thereto. Substituents of known compounds in general formula () will be briefly explained below. In the above formula, the alkyl represented by R ¹ is,
Those with 1 to 7 carbon atoms, and those with 1 to 4 carbon atoms as alkoxy of carbalkoxy,
The alkoxy of carboalkoxyalkyl has 1 to 4 carbon atoms, and the alkyl has 1 carbon number.
As acyl, carbamoyl alkyl has 1 to 4 carbon atoms, alkoxy has 1 to 5 carbon atoms, and hydroxyalkyl has 1 to 7 carbon atoms. The acyl of acyloxy has 1 to 4 carbon atoms, and the acyl of acyloxy has 1 to 4 carbon atoms.
The aryl is phenyl, the aryl of aryloxy is phenyl, the alkyl of alkylthio is 1 to 6 carbon atoms, and the alkyl of alkylsulfinyl is 1 to 6 carbon atoms. can be given. In addition, the alkyl represented by R ² has 1 to 5 carbon atoms, the acyl has 1 to 4 carbon atoms, the alkoxy in carbalkoxy has 1 to 4 carbon atoms, and the alkyl in alkylcarbamoyl has 1 to 4 carbon atoms. as carbon number 1 to 4
The alkyl of dialkylcarbamoyl has 1 to 4 carbon atoms, respectively.
The alkyl in alkylcarbonylmethyl has 1 to 4 carbon atoms, and the alkoxy in alkoxycarbonylmethyl has 1 to 4 carbon atoms.
Examples of the alkyl in alkylsulfonyl include those having 1 to 4 carbon atoms. The alkyl represented by R ³ , R ⁴ and R ⁵ has 1 to 4 carbon atoms, the alkoxy has 1 to 8 carbon atoms, and the alkoxy of alkoxyalkoxy has 1 to 4 carbon atoms. It will be done. Further, the optionally fluorinated alkoxy represented by R ⁴ includes those having 1 to 8 carbon atoms. Among the compounds represented by the above formula (),
R ¹ is hydrogen, methoxy or trifluoromethyl, R ² is hydrogen, R ³ and R ⁵ are the same or different hydrogen or methyl, R ⁴ is fluorinated alkoxy having 2 to 5 carbon atoms, and A compound where m is 1, R ¹ is hydrogen, fluorine, methoxy or trifluoromethyl, R ² is hydrogen, R ³ is hydrogen or methyl, R ⁴ is alkoxy having 3 to 8 carbon atoms, R ⁵ is hydrogen and m is 1, and R ¹ is hydrogen, fluorine, methoxy or trifluoromethyl, R ² is hydrogen, R ³ is alkoxy having 1 to 8 carbon atoms, and R ⁴ is C 1 A compound of 8 to 8 optionally fluorinated alkoxy, in which R ⁵ is hydrogen and m is 1, is a new compound. The substituents of the above novel compound will be explained in detail. The lower alkoxy group represented by R ³ is preferably a lower alkoxy group having 1 to 8 carbon atoms,
Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, puntyloxy, hexyloxy, heptyloxy, octyloxy and the like, with lower alkoxy groups having 1 to 4 carbon atoms being preferred. The lower alkoxy group in the optionally fluorinated lower alkoxy group represented by R ⁴ includes a lower alkoxy group having 1 to 8 carbon atoms, and a preferable example thereof is the same alkoxy group as R ³ above. can be mentioned. Examples of fluorinated lower alkoxy groups include 2,2,2-trifluoroethoxy, 2,2,3,
3,3-pentafluoropropoxy, 1-(trifluoromethyl)-2,2,2-trifluoroethoxy,
2,2,3,3-tetrafluoropropoxy, 2,
2,3,3,4,4,4-heptafluorobutoxy, 2,2,3,3,4,4,5,5-octafluoropentoxy, etc. A hydrogenated lower alkoxy group is preferred. Examples of the position of R ¹ include the 4th and 5th positions, with the 5th position being preferred. Next, a method for producing the above novel compound [hereinafter referred to as formula (')] will be described. The compound has the general formula [In the formula, R ¹ to R ⁵ have the same meanings as above. ] can be produced by subjecting the compound represented by the formula to an oxidation reaction. Examples of the oxidizing agent used here include peracids such as metachloroperbenzoic acid, peracetic acid, trifluoroperacetic acid, and permaleic acid, sodium bromite, and sodium hypochlorite.
Solvents used in the reaction include chloroform,
Halogenated hydrocarbons such as dichloromethane, ethers such as tetrahydrofuran and dioxane,
Examples include amides such as dimethylformamide, water, and the like, which can be used alone or in combination. The amount of the oxidizing agent to be used is preferably approximately equivalent to or slightly in excess of the amount of the compound (). That is, about 1 to 3 equivalents, more preferably about 1 to 1.5 equivalents. The reaction temperature is from ice-cooling to around the boiling point of the solvent used, usually from ice-cooling to room temperature, more preferably from about 0°C to 10°C. Reaction time is usually about 0.1 to 24 hours,
More preferably, it is about 0.1 to 4 hours. The novel target compound (') produced by the above reaction can be isolated and purified by conventional means such as recrystallization and chromatography. The compound may be converted into a pharmacologically acceptable salt by commonly used means. Examples of the salt include hydrochloride, bromate, iodate, phosphate, nitrate, sulfate, acetate, citrate, and the like. Also, the compound () has the general formula [In the formula, R ¹ and R ² have the same meanings as above. ]
Raw material compound and general formula represented by [In the formula, R ³ to ^{R 5} have the same meanings as above, and X represents a halogen atom. ] It can be produced by reacting with the raw material compound represented by. Examples of the halogen atom represented by X include chlorine, bromine, and iodine. This reaction is conveniently carried out in the presence of a base. Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride, alkali metals such as sodium metal, sodium alcoholates such as sodium methoxide and sodium ethoxide, and potassium carbonate and sodium carbonate. carbon salts of alkali metals, organic amines such as triethylamine, etc. Examples of the solvent used in the reaction include alcohols such as methanol and ethanol, and dimethylformamide. The amount of base used in the above reaction is usually slightly in excess of the equivalent amount, but a large excess of base may also be used. That is, about 2 to 10 equivalents, more preferably about 2 to 4 equivalents. The reaction temperature is generally about 0°C to around the boiling point of the solvent used, more preferably about 20°C to 80°C. The reaction time is about 0.2 to 24 hours, more preferably about
0.5 to 2 hours. Next, a method for producing the raw material compound () will be explained. Among the compounds (), compounds in which R ³ and R ⁵ are the same or different and are hydrogen or methyl, and R ⁴ is a fluorinated alkoxy having 2 to 5 carbon atoms or alkoxy having 3 to 8 carbon atoms, are as follows. It can be manufactured in this way. A nitro compound represented by the general formula () [wherein,
R ³ and R ⁵ have the same meanings as above] in the presence of a base, alcohol derivative R ⁴ 'OH () [wherein R ⁴ ' is a fluorinated alkyl having 2 to 5 carbon atoms or Indicates 3 to 8 alkyl. ] By reacting the general formula () [where R ³ ,
R ⁴ and R ⁵ have the same meanings as above] can be obtained. Bases used in the reaction include, for example, alkali metals such as lithium, sodium, and potassium; alkali metal hydrides such as sodium hydride and potassium hydride; alcoholates and potassium carbonate such as potassium t-butoxy and sodium propoxy; carbonates or bicarbonates of alkali metals such as lithium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, alkali metals such as potassium, sodium, lithium, sodium hydroxide,
Examples include alkali hydroxides such as potassium hydroxide. Examples of alcohol derivatives used in the reaction include 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, 2,2,3,3,4,4,
Examples include 5,5-octafluoropentanol. Examples of the solvent used in the reaction include R ⁴ 'OH itself, tethers such as tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, acetonitrile, dimethylformamide, and hexamethylphosphoric triamide. The reaction temperature is appropriately selected from ice-cooling to around the boiling point of the solvent. Reaction time is about 1 to 48 hours. The compound () thus obtained is heated (approximately 80 to 120°C) in the presence of acetic anhydride alone or a mineral acid such as acetic acid or perchloric acid to produce a 2-azezyme compound represented by the general formula (). Toxymethylpyridine derivative [wherein R ³ , R ⁴ and R ⁵ have the same meanings as above. ] is obtained. The reaction time is usually about 0.1
or 10 hours. Then, the 2-hydroxymethylpyridine derivative represented by the general formula () can be produced by subjecting the compound () to alkaline hydrolysis. Examples of the alkali include sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate. Examples of the solvent used include methanol, ethanol, and water. The reaction temperature is usually about 20 to 60°C and the reaction time is about 0.1 to 2 hours. Further, by halogenating the compound () with a chlorinating agent such as thionyl chloride, the general formula () is obtained.
^{A 2 -} halogenomethylpyridine derivative represented by
represents chlorine, bromine or iodine. ] can be manufactured. Examples of the solvent used include chloroform, dichloromethane, and tetrachloroethane. The reaction temperature is usually about 20
to 80°C, and the reaction time is about 0.1 to 2 hours. The produced compound () is a hydrohalide salt of the halogenating agent used, and it is usually preferable to use it immediately for reaction with compound (). Furthermore, among the compounds (), compounds in which R ³ is lower alkoxy having 1 to 8 carbon atoms, R ⁴ is optionally fluorinated alkoxy, and R ⁵ is hydrogen can be produced as follows. . Compound (XI) is obtained by reacting maltol () with an alkyl halide represented by R ³ 'X in the presence of silver oxide, etc., and pyridone derivative (XII) is obtained by reacting (XI) with aqueous ammonia.
can be manufactured. Compound (XII) is converted into a halogen derivative () by direct alkylation with an alkyl halide or by a halogenating agent such as phosphorus oxychloride, and then reacted with a lower alcohol represented by R ⁴ ″OH in the presence of a base. The compound () is then directly halogenated with N-bromosuccinimide, chlorine, etc. to form the compound (), or the compound () is halogenated with an oxidizing agent such as m-chloroperbenzoic acid. (), react with acetic anhydride to form the compound (), and then hydrolyze it to produce the compound (), which can also be led to the compound () with a halogenating agent such as thionyl chloride.Compound () Examples of alkyl halides used in the production of compound (XI) include methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide, butyl iodide, pentyl iodide, hexyl iodide, etc. In addition to the alkyl halides used in the production of compound (XI), examples of the alkyl halides used include 2,2,2-trifluoroethyl iodide, 2,2 , 3,3,3-pentafluoropropyl iodide, 2,2,3,3,-tetrafluoropropyl iodide, 1-(trifluoromethyl)-2,2,2-trifluoroethyl iodide, 2, 2,3,3,4,4,4-heptafluorobityl iodide, 2,2,3,3,4,
Examples include 4,5,5-octafluoropentyl iodide, and the amount used is about 1 to 10 equivalents. Further, examples of the deoxidizing agent include silver oxide, potassium carbonate, sodium carbonate, etc., and examples of the solvent include dimethylformamide, dimethylacetamide, etc., and room temperature is usually used as the reaction condition. The halogenating agents used in the production of compound () include phosphorus oxychloride, phosphorus pentachloride,
Examples include phosphorus tribromide, and the amount used is an equivalent to a large excess, and the reaction temperature is about 50 to 150°C.
Examples of the alcohol used in the reaction from compound () to compound () include methanol, ethanol, and the same alcohol derivatives used in Production Method 1, and the amount used is an equivalent to a large excess, and the base is Sodium or potassium alcoholate, potassium t-butoxide, sodium hydride, etc. are used, respectively. The reaction temperature is appropriately selected from room temperature to the boiling point of the alcohol used. When the compound () is directly brominated with N-bromosuccinic acid, the reaction is preferably carried out under light irradiation, and carbon dioxide tetrachloride, chloroform, tetrachloroethane, etc. are used as the solvent. Examples of the oxidizing agent used in the reaction of compound () to compound () include peracids such as metachloroperbenzoic acid, peracetic acid, trifluoroperacetic acid, and permaleic acid, and hydrogen peroxide.
Solvents used in the reaction include chloroform,
Halogenated hydrocarbons such as dichloromethane, ethers such as tetrahydrofuran and dioxane,
Examples include amides such as dimethylformamide, acetic acid, and water, which can be used alone or in combination. The amount of the oxidizing agent used is determined by the amount of the compound (
) is preferably used in an amount approximately equivalent to or in excess. Preferably it is about 1 to 10 equivalents. The reaction temperature is an appropriate temperature ranging from ice cooling to around the boiling point of the solvent used. The reaction time is usually about 0.1 to 24 hours, more preferably about 0.1 to 4 hours. The production of compound () from compound () is
Compound () with acetic anhydride alone or sulfuric acid,
Heating in the presence of a mineral acid such as perchloric acid (approximately 80 to
120℃). The reaction time is usually 0.1 to 10 hours. Compound () can be produced by alkali hydrolysis of compound (), but examples of the alkali used include sodium hydroxide,
Examples include potassium hydroxide, potassium carbonate, and sodium carbonate. Examples of the solvent used include methanol, ethanol, and water. The reaction temperature is usually about 20 to 60°C and the reaction time is about 0.1 to 2 hours. To produce compound () from compound (), a chlorinating agent such as thionyl chloride, an organic sulfonic acid or an organic phosphoric acid such as methanesulfonyl chloride, p-toluenesulfonyl chloride, and diphenylphosphoryl chloride are used. This is done by using acid chlorides. In the case of a chlorinating agent such as thionyl chloride, an equivalent to a large excess amount of the chlorinating agent is used relative to the compound (). Examples of solvents that can be used include chloroform,
Examples include dichloromethane and tetrachloroethane. The reaction temperature is usually about 20 to 80°C;
The reaction time is about 0.1 to 2 hours. In the case of an acid chloride of an organic sulfonic acid or an organic phosphoric acid, an equivalent to a small excess amount of the chloride is used relative to the compound (), and the reaction is usually carried out in the presence of a base. The base used is triethylamine,
Examples include organic bases such as tributylamine, and inorganic bases such as sodium carbonate, potassium carbonate, and sodium hydrogen carbonate, and the amount used is an equivalent to a small excess. Examples of the solvent used include chloroform, dichloromethane, carbon tetrachloride, acetonitrile, etc., and the reaction temperature and reaction time are under ice cooling.
Appropriate conditions are selected near the boiling point and for several minutes to several hours. The above-mentioned novel benzimidazole compound is
It exhibits excellent gastric acid secretion suppressing effect, gastric mucosal protective effect, and anti-ulcer effect, and has low toxicity, so it can be used in mammals (e.g., mice, rats, rabbits, dogs, cats, etc.).
It can be used to treat gastrointestinal ulcers in humans, etc.). Next, the basic positive inorganic salts of magnesium and calcium used in the present invention will be explained. Examples of the basic inorganic salt of magnesium include heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium aluminate metasilicate, magnesium aluminate silicate, magnesium silicate, magnesium aluminate, and synthetic hydrotal. sites [Mg ₆ Al ₂ (OH) ₁₆・CO ₃・4H ₂ O], alumina hydroxide magnesium [2.5MgO・Al ₂ O ₃・xH ₂ O], etc., and basic inorganic salts of calcium include Examples include precipitated calcium carbonate, calcium hydroxide, etc. These basic inorganic salts of magnesium and calcium may be those whose 1% aqueous solution or suspension has a basic pH (PH 7 or higher). The basic inorganic salts of magnesium and calcium may be blended singly or in combination of two or more, and the blending amount varies depending on the type.
About 1 part by weight of benzimidazole compound
0.3 to 20 parts by weight, preferably about 0.6 to 7 parts by weight. The composition of the present invention may further contain additives, such as excipients (e.g., lactose, corn starch, light anhydrous silicic acid, microcrystalline cellulose, sucrose, etc.), binders (e.g., pregelatinized starch, methylcellulose, etc.). , carboxymethylcellulose, fluoroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.),
Disintegrants (e.g. calcium carboxymethyl cellulose, starch, low substituted hydroxypropyl cellulose, etc.), surfactants (e.g. Tween)
80 (manufactured by Kao Atlas Co., Ltd.), Pluronic F68 (manufactured by Asahi Denka Kogyo Co., Ltd., polyoxyethylene, polyoxypropylene copolymer, etc.), antioxidants (for example, L-
Cysteine, sodium sulfite, sodium ascorbate, etc.), lubricants (eg, magnesium stearate, talc, etc.), etc. are used as additives. The composition of the present invention can be obtained by uniformly mixing the above-mentioned benzimidazole compound, a basic inorganic salt of magnesium and/or calcium, and the above-mentioned additives.
For example, an additive may be mixed in advance with a benzimidazole compound and a basic inorganic salt of magnesium and/or calcium, or a magnesium and/or calcium base may be added to a benzimidazole compound with an additive. A basic inorganic salt of magnesium and/or calcium may be mixed with the benzimidazole compound, as long as the basic inorganic salt of magnesium and/or calcium is finally brought into uniform contact with the benzimidazole compound. The mixture can be formulated into dosage forms suitable for oral administration, such as tablets, capsules, powders, granules, and fine granules, by means known per se. Tablets, granules, and fine granules may be coated by methods known per se for the purpose of taste masking, enteric coating, or persistence. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, and Tween.
80, Pluronic F68, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by Rohm, West Germany, methacrylic acid/acrylic acid copolymer), and pigments such as titanium oxide and red iron oxide are used. Tablets, granules, powders, fine granules, and capsules can be manufactured by conventional methods (for example, methods described in the General Preparations of the Japanese Pharmacopoeia, 10th edition). That is, in the case of tablets, basic inorganic salts of magnesium and/or calcium are added to the benzimidazole compound, excipient, and disintegrant, mixed, and a binder is added to form granules, which are then coated with a lubricant, etc. In addition, it is compressed into tablets. In addition, for granules, extrusion granulation is performed in almost the same way as for tablets, or nonpareil (75% white sugar)
(W/W) and corn starch 25% (W/W)
), water or a binder solution such as sucrose, hydroxypropylcellulose, hydroxypropylmethylcellulose (concentration: approximately 0.5 to 70% (W/
V) while spraying benzimidazole compounds, basic inorganic salts of magnesium and/or calcium, and additives (e.g., sucrose, corn starch, crystalline cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, etc.). It can be obtained by coating a powdery dispersant containing the following: For capsules, simply mix and fill. The preparation thus obtained is
It exhibits excellent stability with little change in appearance and almost no decrease in content even after long-term storage. The stabilized enteric-coated anti-ulcer solid composition of the present invention obtained in this way exhibits excellent gastric acid secretion suppressing action, gastric mucosal protective action, and anti-ulcer action, and has low toxicity, so it can be used in mammals (e.g. It can be used to treat gastrointestinal ulcers in mice, rats, rabbits, dogs, cats, pigs, humans, etc.). When the stabilized enteric anti-ulcer solid composition of the present invention is used to treat gastrointestinal ulcers in mammals, it may be mixed with pharmacologically acceptable carriers, excipients, diluents, etc. as described above. It can be administered orally in the form of capsules, tablets, granules, etc. The dosage is about 0.01 mg to 30 mg/Kg/day as a benzimidazole compound, preferably about
The dose is 0.1 mg to 3 mg/Kg/day. EXAMPLES The present invention will be explained in more detail by reference examples, examples, and experimental examples below, but these are not intended to limit the present invention. Reference example 1 2,3-dimethyl-4-nitropyridine-1-
Oxide (2.0g), methyl ethyl ketone (30ml),
A mixture of 2,2,3,3,3-pentafluoropropanol (3.05 ml), anhydrous potassium carbonate (3.29 g), and hexamethyl phosphoric triamide (2.07 g) was added to
After heating and stirring at ~80°C for 4.5 days, insoluble matter was filtered off and concentrated. Water was added to the residue, extracted with ethyl acetate, dried over magnesium sulfate,
The solvent was distilled off, the residue was applied to a column of silica gel (50 g), and chloroform-methanol (10:
1) and recrystallized from ethyl acetate-hexane to give 2,3-dimethyl-4-(2,
2.4 g of colorless needles of 2,3,3,3-pentafluoropropoxy)pyridine-1-oxide were obtained. Melting point: 148-149°C Compound () was produced from starting compound () by the same method as above.

[Table] Reference example 2 2,3-dimethyl-4-(2,2,3,3,3
Concentrated sulfuric acid (2 drops) was added to a solution of -pentafluoropropoxy)pyridine-1-oxide (2.5 g) and acetic anhydride (8 ml), and the mixture was stirred at 110°C for 2 hours.
Concentrated. The residue was dissolved in methanol (30 ml), a 2N solution of sodium hydroxide in water (20 ml) was added, and the mixture was stirred at room temperature for 2 hours. After concentration, water was added and extracted with ethyl acetate. After drying with magnesium acetate, the solvent was distilled off and silica gel (50%
g), eluted with chloroform-methanol (10:1), and recrystallized from isopropyl ether to yield 2-hydroxymethyl-3-methyl-4-(2,2,3,3,3-pentafluoropropoxy). ) 1.6 g of a brown oil of pyridine was obtained. NMR spectrum ( _CDCl3 ) δ: 2.07 (3H,
s), 4.28 (1H, brs), 4.49 (2H, t, J=12Hz),
4.67 (2h, s), 6.69 (1H, d, J=5Hz), 8.34
(1H, d, J=5Hz) Compound () was produced from compound () by the same method as above.

[Table] Reference example 3 2-hydroxymethyl-3-methyl-4-(2,
Thionyl chloride (0.2 ml) was added to a chloroform solution (10 ml) of 2,3,3,3-pentafluoropropoxy)pyridine (350 mg), heated under reflux for 30 minutes, concentrated, and the residue was dissolved in methanol (5 ml). , 2-mercaptobenzimidazole (200
mg), 28% sodium methoxide solution (1 ml), and methanol (6 ml), and the mixture was heated under reflux for 30 minutes.
Methanol was distilled off, water was added, and the mixture was extracted with ethyl acetate, washed with dilute sodium hydroxide solution, and dried over magnesium sulfate. After distilling off the solvent, it was applied to a column of silica gel (20 g), eluted with ethyl acetate-hexane (2:1), and recrystallized from ethyl acetate-hexane to give 2-[[3-methyl-4-(2,2 , 3,3,3-pentafluoropropoxy)-2-pyridyl]methylthio]benzimidazole hemihydrate (370 mg) was obtained. Melting point 145-146℃. Hereinafter, in the same way as above, create the compounds () and ()
Compound () was produced by reacting with

[Table] Reference example 4 2-[[3-methyl-4-(2,2,3,3,3
-Pentafluoropropoxy)-2-pyridyl]methylthio]benzimidazole (2.2 g) in chloroform (20 ml) was cooled with ice, and a solution of m-chloroperbenzoic acid (1.3 g) in chloroform (15 ml) was added.
After adding dropwise over 30 minutes, the reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution. After drying with magnesium sulfate, it was concentrated, applied to a column of silica gel (50 g), eluted with acetic acid ethyl ester, and acetone-
When recrystallized from isopropyl ether, 2-
Pale yellow prism of [[3-methyl-4-(2,2,3,3,3-pentafluoropropoxy)-2-pyridyl]methylsulfinyl]benzimidazole (hereinafter sometimes referred to as the compound) Akira
1.78g was obtained. Melting point: 161-163°C (decomposition) Compound () (hereinafter sometimes referred to as compound, compound, or compound) was produced from compound () in the same manner.

[Table] Example 1 Mix the compounds shown below, magnesium hydroxide, L-cysteine, cornstarch, and lactose, then add 1/2 amount of microcrystalline cellulose, light anhydrous silicic acid, and magnesium stearate and mix well. Thereafter, it was compressed and molded using a dry granulator (roller compactor, manufactured by Freund, Japan).
This material was ground in a mortar and passed through a round sieve (16 mesh), then the remaining amount of microcrystalline cellulose, light anhydrous silicic acid, and magnesium stearate were added and mixed, and then processed using a rotary tablet machine (manufactured by Kikusui Seisakusho). Tablets of 250 mg each were manufactured. Composition in 1 tablet Compound 50 mg Magnesium hydroxide 30 mg L-cysteine 20 mg Corn starch 20 mg Lactose 65.2 mg Microcrystalline cellulose 60 mg Light anhydrous silicic acid 1.8 mg Magnesium stearate 3.0 mg Total 250.0 mg Example 2 In the method of Example 1, the compound Tablets were manufactured using omeprazole (Note) instead of . (Note) 5-Methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole Example 3 Among the following compositions, the compound, precipitated calcium carbonate, cornstarch, lactose and Hydroxypropyl cellulose was mixed, water was added thereto, kneaded, vacuum dried at 40°C for 16 hours, ground in a mortar, and passed through a 16-mesh sieve to form granules. Magnesium stearate was added to this, and tablets of 200 mg each were manufactured using a rotary tablet press (manufactured by Kikusui Seisakusho). Composition in 1 tablet Compound 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 In the method of Example 3, Timoprazole ( Note) Tablets were manufactured using (Note) [(2-pyridyl)methylsulfinyl]
Benzimidazole Example 5 After thoroughly mixing the substances with the following composition ratios, water was added and kneaded, and the mixture was granulated using an extrusion granulator (manufactured by Kikusui Seisakusho, screen diameter 1.0 mmφ), and immediately processed using a Marmerizer (Fuji Paudal Co., Ltd., screen diameter 1.0 mm). The granules were made into spherical granules at 1,000 rpm), vacuum dried at 40°C for 16 hours, and sieved through a round sieve to obtain granules of 12 to 42 mesh. Composition in 200 mg of granules Compound 30 mg Heavy magnesium carbonate 20 mg Corn starch 80 mg Microcrystalline cellulose 20 mg Carboxymethyl cellulose calcium 10 mg Hydroxypropyl cellulose 10 mg Pluronic F68 4 mg Lactose 26 mg Water (0.1 ml) Total 200 mg Example 6 In the method of Example 5, the compound Instead, the compound was used to produce granules. Example 7 The granules obtained in Example 3 were coated with an enteric coating liquid having the following composition in a fluidized spray dryer (manufactured by Okawara Co., Ltd.) under conditions of an air supply temperature of 50°C and a granule temperature of 40°C to obtain enteric granules. Ta. Capsules were prepared by filling 260 mg of this product into No. 1 hard capsules using a capsule filling machine (Parke Davis Company, USA). Enteric coating liquid composition Eudragit L-30D
138mg (solid ingredients 41.4mg) Talc 4.1mg Polyethylene glycol 6000 12.4mg Tween 80 2.1mg Water 276μ Composition of enteric-coated granules Granules of Example 5 200mg enteric coating 60mg total 260mg Composition of capsules Enteric-coated granules 260mg No. 1 hard capsule 76mg total 336mg Example 8 Among the following compositions, compounds, magnesium carbonate,
White sugar, cornstarch, and crystalline cellulose were mixed well to prepare a dispersant. Centrifugal fluid coating granulation equipment (manufactured by Freund Sangyo Co., Ltd., CF-
360), and while spraying a hydroxypropyl cellulose solution (4% (W/V)), the mixture was coated with the above-mentioned dusting agent to obtain spherical granules.
The spherical granules were vacuum dried at 40° C. for 16 hours and passed through a circular sieve to obtain granules of 12 to 32 meshes. Composition of 190 mg of granules Nonpareil 75 mg Compound 15 mg Magnesium carbonate 15 mg White sugar 29 mg Corn starch 27 mg Crystalline cellulose 27 mg Hydroxypropyl cellulose 2 mg Water (0.05 ml) Total 190 mg Example 9 The granules obtained in Example 8 were coated with an enteric coating liquid having the following composition. was coated in a fluidized spray dryer (manufactured by Okawara Co., Ltd.) at a supply air temperature of 50°C and a granule temperature of 40°C to obtain enteric granules. Capsules were prepared by filling 240 mg of the granules into No. 2 hard capsules using a capsule filling machine (manufactured by Parke Davis). Composition of enteric coating liquid Oitoragituto L-30D 104.7mg (solid component 31.4mg) Talc 9.6mg Polyethylene glycol 6000 3.2mg Tween 80 1.6mg Titanium oxide 4.2mg Water (220μ) Composition of enteric granules Granules of Example 8 190mg enteric Film 50mg total 240mg Capsule composition Enteric coated granules 240mg No. 2 hard capsule 65mg total 305mg Experimental example 1 Granules were manufactured according to the method of Example 5 and heated to 75% at 50℃.
Changes in appearance were observed after 1 week of RH. However, products in which heavy magnesium carbonate was replaced with lactose, or products in which the following attachments were used were also produced in the same manner and aged over time.

[Table]: 〃 Violent As a result, almost no change in appearance was observed in the samples to which the additives of the present invention were added. Experimental Example 2 According to the method of Example 5, the compound was
Compound, compound omeprazole, produced granules changed to timoprazole, 50℃, 75%RH, 1
Changes in appearance were observed after a week. As a control, a product in which heavy magnesium carbonate was replaced with lactose was also produced and similarly aged over time.

[Table] -: No change in appearance: Severe As a result, the compound, omeprazole, timoprazole compound, and the composition of the present invention were all stable. Experimental Example 3 In Examples 3 and 5, the basic Mg inorganic salt or Ca inorganic salt was changed in various ways, or lactose was used as a control, and the preparations in Example 7 were prepared and heated at 50°C and 75% RH. , 1 week and 40
Changes in appearance and content (residual rate) were measured after storage at ℃ for 6 months.

[Table] As a result, the composition of the present invention showed no change in appearance;
It became clear that the content was also stable. Effects of the Invention In the present invention, a physically stable enteric-coated anti-ulcer solid composition can be obtained by blending a basic inorganic salt of magnesium and/or calcium with a benzimidazole compound.

Claims (1)

[Claims] 1. Acid-labile 2-[(2-
A stabilized enteric-coated anti-ulcer solid composition comprising a basic inorganic salt of magnesium and/or calcium as a stabilizer, which is uniformly brought into contact with a pyridyl)methylsulfinyl]benzimidazole compound. 2. The basic inorganic salt is heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium aluminate metasilicate, magnesium silicate, synthetic hydrotalcite, alumina magnesium hydroxide, precipitated calcium carbonate or calcium hydroxide. A composition according to claim 1. 3. Claim No. 3 in which the basic inorganic salt of magnesium and/or calcium is blended in an amount of 0.3 to 20 parts by weight per 1 part by weight of the 2-[(2-pyridyl)methylsulfinyl]benzimidazole compound. Composition according to item 1. 4. The composition according to claim 1, which is a tablet, granule or fine granule. 5. The composition of claim 1 coated with hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose or hydroxypropylcellulose. 6. The composition according to claim 1 coated with an enteric coating agent. 7. The composition according to claim 6, wherein the enteric coating agent is cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, or a methacrylic acid/acrylic acid copolymer.