JPH0725767A - Urease inhibitor - Google Patents

Abstract

PURPOSE:To obtain an urease inhibitor derived from bacteria of the genus Helicobacter or Ureaplasma. CONSTITUTION:The unease inhibitor contains a 2-[(2-pyridyl) methylsulfinyl]benzimidazole based compound or its salt having activities against ulcers and is derived from bacteria of the genus Helicobacter or Ureaplasma. The urease inhibitor suppresses ammonia production by bacteria of the genus Helicobacter and growth of bacteria of the genus Ureaplasma and is able to be used for preventing and treating diseases caused by those bacteria.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a urease inhibitor. The urease inhibitor of the present invention suppresses the production of ammonia by Helicobacter spp., Inhibits the growth of Ureaplasma spp, and is used for the treatment and prevention of gastritis, gastric ulcer, non-gonococcal urethritis, chronic prostatitis, etc. To be

[0002]

Which is a kind of BACKGROUND OF THE INVENTION Helicobacter (Helicobacter) genus, Helicobacter pylori (Helicobacter p
ylori ) colonizes the gastric mucosa and develops. Urease possessed by the bacterium hydrolyzes urea in body fluids to produce ammonia. This ammonia acts on the gastric mucosa and acts as an aggravating factor for gastritis and gastric ulcer. {Gastroenterology, Volume 96 [Suppliment], A252 (1989) and Infection and Immunity (Infection and
Immunity), 58, 1992-1994 (1990)
Year) reference}, which is a kind of urea plasma (Ureaplasma) spp., Ureaplasma utility Kum (Uleaplasma urealytic
um ) is presumed to be the causative bacterium of non-gonococcal urethritis, chronic prostatitis, etc. Ureaplasma urealyticum ( Ul
eaplasma urealyticum ) requires urea for its development. This bacterium has urease and obtains energy for growth by hydrolyzing urea. [Journal of Bacteriol
ogy), 144, 830-832 (1980)].

[0003]

The object of the invention is to be Solved by Helicobacter (Heli
Effective inhibition of urease produced by the bacterium ( cobacter ) can suppress the production of ammonia, which acts as an aggravating factor for gastritis and gastric ulcer. Further, Ureaplasma if effectively inhibit urease (Ureaplasma) genus, for example, non-gonococcal urethritis, urea is estimated to cause bacteria such as chronic prostatitis plasma urea utility Kum (Ul
eaplasma urealyticum ) and can be used for the treatment of these diseases. However, Helicobacter (Helicobacter) belonging to the genus or urea plasma (Ureaplas
Until now, no compound has been known that effectively inhibits urease of genus ma ).

[0004]

[Means for Solving the Problems] In view of such circumstances,
The present inventors have found that Helicobacter (Helicobacter) genus or Ureaplasma (Ureaplasma) was intensively studied urease effectively inhibit compounds of the genus, having antiulcer activity 2- {2- [3- methyl-4 -(2,2,2
- trifluoroethoxy) pyridyl] methylsulfinyl} benzimidazole (hereinafter referred to as AG-1749) and 4-methyl-3- (2,2,2-trifluoroethoxy) -5 H - pyrido [1 ', 2' : 4, 5]
It was found that [1,2,4] thiadiano [2,3- a ] benzimidazol-13-ium-tetrafluoroborate (hereinafter referred to as AG-2000) and the like have the activity. [Japanese Journal of Bacteriology 48 (1), 1
993, p. 304 and Antimicrobial Agens and Chemotherapy.
ts and Chemotherapy), 37, 769-774 (1993)] and based on these findings, further research has led to the completion of the present invention. That is, the present invention includes 1) a 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound (hereinafter also referred to as a benzimidazole compound) having an anti-ulcer action, or a Helicobacter genus containing a salt thereof. And a urease inhibitor derived from a bacterium belonging to the genus Ureaplasma, 2) a 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound having an antiulcer action is represented by the general formula (I).

[Chemical 3] [In the formula, ring A may be substituted, R ¹ and R ³ are the same or different and each represents a hydrogen, an alkyl group or an alkoxy group, and R ² is a hydrocarbon residue which may have a substituent. Each of the above] is a compound represented by 1), the urease inhibitor according to 1), 3) the urease inhibitor according to 2) above, wherein A ring is unsubstituted, 4) the above 2), wherein R ¹ is an alkyl group. Urease inhibitor, 5) the urease inhibitor described in 2) above, wherein R ¹ is a methyl group, 6) the urease inhibitor described in 2) above, wherein R ³ is hydrogen, 7) the above 2 wherein R ³ is an alkyl group 8) the urease inhibitor, 8) the urease inhibitor according to 2) above, wherein R ³ is a methyl group, 9) the urease inhibitor according to 2) above, wherein R ² is an optionally fluorinated alkyl group.

10) A 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound having an antiulcer action is represented by the general formula (I ').

[Chemical 4] [In the formula, ring A'may be substituted, R ¹ 'and R ³ ' may be the same or different and each represents a hydrogen atom, an alkyl group or an alkoxy group, and R ² 'may have a substituent. Hydrogen radicals, X ⁻ represents an anion respectively] 11) The urease inhibitor described in 1) above, 11) the urease inhibitor described in 10) above in which the A ′ ring is unsubstituted, 12) R ¹ urease inhibitors of the 10), wherein the 'is above 10) urease inhibitor 13 according) R ¹ is an alkyl group' is a methyl group, 14) urease inhibition of the 10), wherein R ³ 'is hydrogen Agent, 15) the urease inhibitor described in 10) above, wherein R ³ ′ is an alkyl group, 16) the urease inhibitor described in 10) above, wherein R ³ ′ is a methyl group, 17) R ² ′ is fluorinated 10) which is an optionally substituted alkyl group 18) the urease inhibitor described above, 18) the urease inhibitor described in 1) above, wherein the Helicobacter genus is Helicobacter pylori, and 19) the urease inhibitor described in 1) above, wherein the Ureaplasma genus is Ureaplasma urealyticum. Regarding Examples of the 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound having an anti-ulcer activity used in the present invention include, for example, 2 having an anti-ulcer activity and being acid-labile.
- 5 H with a [(2-pyridyl) methylsulfinyl] benzimidazole derivatives and antiulcer activity - pyrido [1 ', 2': 4,5] [1,2,4] Chiajiano [2,3-a] Benz Imidazole-13-ium derivative etc. are mentioned. Specifically, for example, JP-A-61-5
0978, 62-277322, 63-301.
No. 816, No. 59-181277, No. 54-1417.
83, 52-62275, 61-115080.
No. 62-258320 and 62-258316.
Nos. 64-79177 and 57-53406, JP-A-5-59043 and JP-A-58-13.
5881, European Patent Nos. 166287, 515,365, and Japanese Patent Laid-Open Nos. 61-7281.
Nos. 62-277392 and the like, and compounds produced by a method similar to the method described in each publication are also used in the present invention.

[0006] More specifically, for example, the general formula (I)

[Chemical 5] [In the formula, ring A may be substituted, R ¹ and R ³ are the same or different and each represents a hydrogen, an alkyl group or an alkoxy group, and R ² is a hydrocarbon residue which may have a substituent. Each of these is shown]. Furthermore, the general formula (I ')

[Chemical 6] [In the formula, ring A'may be substituted, R ¹ 'and R ³ ' may be the same or different and each represents a hydrogen atom, an alkyl group or an alkoxy group, and R ² 'may have a substituent. A hydrogen residue and X ⁻ each represents an anion]. In the above general formulas (I) and (I ′), the substituent when ring A or ring A ′ is substituted is preferably, for example, a hydroxyl group, a halogen atom, an optionally substituted alkyl group, or a substituted group. And optionally substituted cycloalkyl groups, optionally substituted alkenyl groups, optionally substituted alkoxy groups and the like. Next, each of the above substituents will be described. Halogen atoms include fluorine, chlorine, bromine and iodine. Of these, fluorine and chlorine are preferable. Further, fluorine is particularly preferable.
Examples of the alkyl group in the optionally substituted alkyl group include a linear or branched alkyl group having 1 to 10 carbon atoms. Specific examples of the alkyl group include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n.
-Pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like. Of these, a linear or branched alkyl group having 1 to 6 carbon atoms is preferable. Further, a linear or branched alkyl group having 1 to 3 carbon atoms is particularly preferable. Examples of the substituent in the alkyl group include halogen, nitro, amino group (which may have 1 or 2 acyl groups, alkyl groups and the like), cyano group, hydroxy group, carboxy group, amidino. Group, guanidino group, carbamoyl group and the like.

The cycloalkyl group in the optionally substituted cycloalkyl group has, for example, 3 to 7 carbon atoms.
The cyclicle alkyl group of Specific examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The substituent in the cycloalkyl group includes
For example, halogen, nitro, amino group (which may have 1 to 2 substituents such as alkyl group and acyl group), cyano group, hydroxy group, carboxy group, amidino group, guanidino group, carbamoyl group, etc. Can be mentioned. The alkenyl group in the optionally substituted alkenyl group is preferably a linear or branched alkenyl group having 2 to 16 carbon atoms. Specific examples of the alkenyl group include allyl, vinyl, crotyl, 2-penten-1-yl, 3-penten-1-yl, 2-hexen-1-yl,
3-hexen-1-yl, 2-methyl-2-propene-
1-yl, 3-methyl-2-buten-1-yl and the like can be mentioned. Of these, a linear or branched alkenyl group having 2 to 6 carbon atoms is preferable. Further, a linear or branched alkenyl group having 2 to 4 carbon atoms is preferable. Examples of the substituent in the alkenyl group include halogen, nitro, amino group (which may have 1 or 2 alkyl groups, acyl groups and the like), cyano group, amidino group, guanidino group and the like. Groups. The alkenyl group includes isomers (E, Z isomers) related to the double bond. Examples of the alkoxy group in the optionally substituted alkoxy group include an alkoxy group having 1 to 10 carbon atoms. Specific examples of the alkoxy group include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, nonyloxy. , Cyclobutoxy, cyclopentoxy, cyclohexyloxy and the like. Of these, an alkoxy group having 1 to 6 carbon atoms is preferable.
Further, an alkoxy group having 1 to 3 carbon atoms is particularly preferable. Examples of the substituent in the alkoxy group include halogen, nitro, amino group (alkyl group, acyl group, etc.
You may have as an individual substituent. ), Amidino group, guanidino group and the like.

Examples of the halogen of the substituent on the above alkyl group, cycloalkyl group, alkenyl group and alkoxy group include chlorine, bromine, fluorine and iodine.
The alkyl group in the alkylamino group, which is a substituent on the alkyl group, cycloalkyl group, alkenyl group and alkoxy group, is preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n.
-Pentyl, isopentyl, n-hexyl, isohexyl and the like can be mentioned. Among them, a linear or branched alkyl group having 1 to 4 carbon atoms is particularly preferable. Examples of the acyl group in the acylamino group that is a substituent on the alkyl group, cycloalkyl group, alkenyl group and alkoxy group include an acyl group derived from an organic carboxylic acid. Of these, an alkanoyl group having 1 to 6 carbon atoms is preferable. Specific examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like. Among them, an alkanoyl group having 1 to 4 carbon atoms is particularly preferable. The number of substituents on the alkyl group, cycloalkyl group, alkenyl group and alkoxy group is 1 to 6, preferably 1 to 3. Specific examples of the substituted alkyl group include, for example, trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
Methoxyethyl, ethoxyethyl, 1-methoxyethyl,
2-methoxyethyl, 2,2-dimethoxyethyl, 2,2-
Examples include diethoxyethyl, 2-diethylphosphorylethyl and the like. Of these, difluoromethyl, trifluoromethyl and hydroxymethyl are preferable. Furthermore, trifluoromethyl is particularly preferable.

Specific examples of the substituted cycloalkyl group include 2-aminocyclopropan-1-yl, 4
-Hydroxycyclopentan-1-yl, 2,2-difluorocyclopentan-1-yl and the like can be mentioned. Specific examples of the substituted alkenyl group include, for example, 2,2
-Dichlorovinyl, 3-hydroxy-2-propene-1-
And 2-methoxyvinyl. Specific examples of the substituted alkoxy group include, for example, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-methoxyethoxy, 4-chlorobenzyloxy, 2- (3,4-dimethoxyphenyl). Examples include ethoxy and the like. Of these, difluoromethoxy is particularly preferred. The position of the substituent on the benzene ring is 4
Position and 5 position, of which 5 position is preferable (the number of the position on the benzene ring is described in the general formulas (I) and (I ′)). Examples of the alkyl group represented by R ¹ , R ³ , R ¹ ′ or R ³ ′ include a linear or branched alkyl group having 1 to 10 carbon atoms. Specific examples of the alkyl group include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,
Examples include neopentyl, hexyl, heptyl, octyl, nonyl and decyl. Of these, a linear or branched alkyl group having 1 to 6 carbon atoms is preferable. Further, a linear or branched alkyl group having 1 to 3 carbon atoms is particularly preferable.

Examples of the alkoxy group represented by R ¹ , R ³ , R ¹ 'or R ³ ' include an alkoxy group having 1 to 10 carbon atoms. Specific examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, nonyloxy. , Cyclobutoxy, cyclopentoxy, cyclohexyloxy and the like. Of these, an alkoxy group having 1 to 6 carbon atoms is preferable. Further, an alkoxy group having 1 to 3 carbon atoms is particularly preferable. R ² or R ² ′
The hydrocarbon residue of the hydrocarbon residue which may have a substituent has a linear or branched carbon number of 1
~ 6 alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pen
Tyl, isopentyl, hexyl, etc.), an alkenyl group having 2 to 6 carbon atoms (eg, vinyl, allyl, 2-butenyl, methylallyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl, etc.), carbon number 2 ~ 6 alkynyl groups (eg, ethynyl, propargyl, 2-butyne-1
-Yl, 3-butyn-2-yl, 1-pentyn-3-yl, 3-pentyn-1-yl, 4-pentyn-2-yl, 3-hexyn-1-yl, etc.), carbon number 3-6 A cycloalkyl group (eg, cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, etc.), carbon number 3-6
A cycloalkenyl group (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.), an aralkyl group having 7 to 13 carbon atoms (eg, benzyl,
1-phenethyl, 2-phenethyl, etc.), 6 to 1 carbon atoms
And aryl groups of 0 (eg, phenyl, naphthyl, etc.).

Examples of the substituent include a C _6-10 aryl group (eg, phenyl, naphthyl etc.), amino, a C _1-6 alkylamino group (eg, methylamino, ethylamino,
Isopropylamino etc.), diC _1-6 alkylamino group (eg dimethylamino, diethylamino etc.), azide, nitro, halogen (eg fluorine, chlorine, bromine, iodine etc.), hydroxyl, C _1-4 alkoxy group (eg (Eg, methoxy, ethoxy, etc.), C _6-10 aryloxy group (eg, phenoxy, naphthyloxy, etc.), C _1-6 alkylthio group (eg, methylthio, ethylthio, propylthio, etc.), C _6-10 arylthio group (eg. , Phenylthio,
Naphthylthio), cyano, carbamoyl group, carboxyl group, C _1-4 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), C _7-11 aryloxycarbonyl group (eg, phenoxycarbonyl,
1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl etc.), carboxy-C _1-4 alkoxy group (eg carboxymethoxy, 2-carboxyethoxy etc.), C _1-6 alkanoyl group (eg formyl, acetyl, propionyl, Isopropionyl, butyryl, pentanoyl, hexanoyl, etc., C _7-11 aroyl group (eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C _6-10 arylsulfonyl group (eg, benzenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), C _1-6 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl, etc.), C _6-10 arylsulfinyl group (eg, benzenesulfinyl, 1
-Naphthylsulfinyl, 2-naphthylsulfinyl, etc.), C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc.), 5 or 6 containing 1 to 4 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) Membered heterocyclic groups (eg, 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4-thiadiazol-2-yl, 1-methyl-5-tetrazolyl, etc.), hetero 1 atom (eg nitrogen, oxygen, sulfur, etc.)
A 4- or 5-membered heterocyclic carbonyl group (eg, 2-
Furoyl, 2-thenoyl, nicotinyl, isonicotinyl, etc.), heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) 1
A 5- or 6-membered heterocyclic thio group containing 4 to 4 (eg, 4-pyridylthio, 2-pyrimidylthio, 1,3,4-thiadiazol-2-ylthio, 1-methyl-5-tetrazolylthio, etc.) and the like, and The heterocyclic thio group may be condensed with a benzene ring to form a bicyclic condensed ring thio group (eg, 2-benzothiazolylthio, 8-quinolylthio, etc.). R ⁴ is a di-substituted carbamoyl group,
When a thiocarbamoyl group or a sulfamoyl group is shown, a nitrogen-containing heterocyclic ring (eg, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4 together with the nitrogen atom of the carbamoyl group, thiocarbamoyl group, or sulfamoyl group) -Methylpiperazin-1-yl,
4-phenylpiperazin-1-yl and the like) may be formed. The number of substituents is from 1 to 5, preferably 1
To 3.

Examples of the anion represented by X ⁻ include halogen ions (eg, iodine ions, brom ions,
(Chlorine ion, etc.), sulfur ion, phosphate ion, nitrate ion, perchlorate ion, tetrafluoroborate ion, methane sulfate ion, p-tolyl sulfate ion, benzene sulfate ion, hydroxide ion, carboxyl of organic acid Rate ion (eg, oxalate ion, maleate ion, fumarate ion, succinate ion, citrate ion, lactate ion, trifluoroacetate ion, lactobionate ion, acetate ion, propionate ion, tartarate ion) , Ethylsuccinate ion, etc.) and the like. Examples of the benzimidazole compound used in the present invention include those disclosed in JP-A-61-50978 and JP-A-6-50978.
2-277322, 63-301816, 59.
No. 181277, No. 54-141783, No. 52-
62275, 61-115080, 62-25
No. 8320, No. 62-258316, No. 64-791
77, 57-53406, JP-A-5-5
9043, JP-A-58-135881, JP-A-166287, JP-A-519365, JP-A-61-7281 and JP-A-62-12773.
It is produced by the method described in each publication of No. 92 or the like and a method similar thereto. The benzimidazole compound used in the present invention can also be used as a physiologically acceptable salt. Examples of physiologically acceptable salts include salts with inorganic bases, salts with organic bases, salts with basic amino acids and the like. Inorganic bases that can form these salts include alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.), and organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, N, N
-Dibenzylethylenediamine, ethanolamine, diethanolamine, trishydroxymethylaminomethane, dicyclohexylamine and the like, and basic amino acids such as arginine and lysine. These salts can be produced by the method described in EP 124495 or a method analogous thereto.

The urease inhibitor of the present invention has low toxicity and can be used safely. The urease inhibitor of the present invention is administered to warm-blooded mammals (eg, mice, dogs, cows, horses, monkeys, humans, etc.) to suppress the production of ammonia, which acts as an aggravating factor for gastritis and gastric ulcer, for example. It is possible,
Also Uleaplasma u
realyticum) and can be used for the prevention and treatment of non-gonococcal urethritis, chronic prostatitis, etc. The dose of the urease inhibitor of the present invention may be any effective amount of the benzimidazole compound or its salt. For example, about 0.5 mg to 3 g / day, preferably about 5 mg of benzimidazole compound per adult (body weight 50 kg)
To 1.5 g / day, particularly preferably about 5 mg to 1 g
/ Day. The urease inhibitor of the present invention can take various dosage forms. Examples of the dosage form include oral preparations (eg, capsules, tablets, granules, powders, etc.), parenteral preparations (eg, injections, etc.) and the like. For example, in order to prepare a preparation for oral administration, a benzimidazole compound or a salt thereof can be prepared according to a method known per se, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrating agent (eg, starch, calcium carbonate, etc.), Binder (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) is added and compression molded, then required For the purpose of taste masking, enteric coating or persistence, coating can be carried out by a method known per se to give a preparation for oral administration. Examples of the coating agent include hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, and Bluronic F6.
8. Dyes such as cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (manufactured by Rohm Co., Germany, methacrylic acid / acrylic acid copolymer) and titanium oxide and red iron oxide are used. Preferably, an oral preparation can be prepared by, for example, the method described in JP-B-3-38247 or a method similar thereto. It is also effective to parenterally administer a benzimidazole compound or its salt as an injection. In that case, the concentration of the benzimidazole compound or its salt is 0.1 to 20 mg / ml, especially 2
It is preferably 10 mg / ml. The injection of a benzimidazole compound or a salt thereof is preferably
For example, it can be produced by the method described in JP-A-3-173817 or a method similar thereto.

[0014]

EXAMPLES Next, the present invention will be described more specifically with reference to examples, but the scope of the present invention is not limited by these. Example 1 Non-pareil (sugar core coated with 75 parts by weight of sucrose by 25 parts by weight of corn starch by a method known per se)
28 mesh) 1650 g, CF device (CF-360,
Made in Freund, Japan) and the rotor speed is 25
At 0 rpm, 1050 ml of hydroxypropyl cellulose (2% (w / v)) was sprayed at 30 ml / min at room temperature, and a spraying agent having the following composition obtained by premixing was spray-coated at 60 g / min.
Vacuum drying was performed at 16 ° C for 16 hours, and spherical nucleated granules of 14 to 32 mesh were obtained using a round sieve. [Spraying agent] AG-1749 450 g Mcnesium carbonate 336 g Graniu sugar 897 g Corn starch 546 g L-HPC 600 g (Hydroxypropoxysyl group substitution degree: 10.0-13.0% (w / w), average residual particle diameter 30 μm or less) ──────────────────────────────── 3800 g of the obtained granules were applied to a fluidized bed coating machine (Okawara, Japan). Insert, control the air temperature at 65 ° C and the product temperature at 40 ° C, and 50 ml of enteric film solution of the following composition
/ Min to spray enteric coating to obtain enteric coated nucleated granules. Talc and light chamber silicic acid anhydride were mixed with the granules and filled into No. 1 hard capsules using a capsule filling machine (Park Davis, USA) to produce capsules. [Enteric film liquid] Eudragit L30D-55 2018g (solid content 650g) Talc 182g Polyethylene glycol 60g Titanium oxide 60g Tween 80 27g Water 4230ml ━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━━━━━

[Composition in 1 Capsule] Enteric coated granules 368.8 mg Compound (I) 30.0 mg Magnesium carbonate 22.4 mg Nonpareil 110.0 mg Graniu sugar 59.8 mg Corn starch 36.4 mg L-HPC 40.0 mg Hydroxypropyl cellulose 1.4 mg Eudragit L30D-55 44.6 mg Talc 13.4 mg Polyethylene glycol 6000 4.4 mg Titanium oxide 4.4 mg Tween 80 2.0 mg Talc 0.6 mg Light anhydrous silicic acid 0.6 mg No. 1 hard capsule 79.0 mg --- ───────────────────────────── Total 449.0 mg Adult male boys take 1 capsule of this capsule after each meal.

Example 2 Of the following compositions, AG-1749, precipitated calcium carbonate,
Mix cornstarch, lactose and hydroxypropyl cellulose, add water and knead.
It was vacuum dried at 0 ° C. for 16 hours, ground in a mortar, and passed through a 16-mesh sieve to give granules. Magnesium stearate was added to this, and 1 with a rotary tableting machine (Kikusui Seisakusho)
200 mg tablets were produced per tablet. Composition in one tablet AG-1749 30 mg Precipitated calcium carbonate 50 mg Corn starch 40 mg Lactose 73.4 mg Hydroxypropyl cellulose 6 mg Magnesium stearate 0.6 mg Water (0.05 ml) ──────────────── ─────────────── Total 200.0mg

Example 3 After thoroughly mixing substances having the following composition ratios, water was added and kneaded, and an extrusion granulator (Kikusui Seisakusho, screen diameter 1.
(0 mmφ) and immediately granulated with Marumerizer (Fuji Paudal Co., 1000 rpm) to make spherical granules. 4
It was vacuum dried at 0 ° C. for 16 hours, and sieved with a round sieve to give granules of 12 to 42 mesh. Composition in granules 200 mg AG-1749 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 200mg

Example 4 AG-1749 (3 g) was dispersed in distilled water for injection to give 1N.
-Dissolved in 9 ml sodium hydroxide. To this solution, 100 ml of distilled water for injection, 6 g of mannitol and 1 g of N-methylglucamine were added and dissolved. The total volume is 200 ml
Distilled water for injection was added to the mixture to remove the bacteria, and the bacteria were removed by a conventional method. The obtained filtrate was dispensed in 2 ml aliquots into 17 cm ³ volume vials and then freeze-dried. When the lyophilized powder contained in this vial was used, 1N-hydrochloric acid 0.72 ml and polyethylene glycol 400 (3 g) were added to a total amount of 10 m.
It is dissolved in distilled water for injection so that the volume becomes 1 to prepare an injection solution.

Experimental Example Measurement of Urease Inhibitory Activity Test Method Helicobacter pylori NC
A viable bacterium of TC 11637 (about 5 × 10 ⁸ bacterium) was suspended in distilled water (hereinafter, abbreviated as DW, 1 ml) from which oxygen was removed by boiling after boil treatment, and stirred for 60 seconds with a vortex mixer. Centrifuge this suspension to 1
It was spun down at 0000 xg and 4 ° C for 20 seconds. The resulting supernatant is diluted with DW and divided into 25 μl fractions, each containing 1 unit of urease. 25m for each fraction
M phosphate buffer (25 μl, pH 6.0) and 25, 12.5, 6.25, 3.12, 1.56, 0.7, respectively
8, 0.39, 0.2 μM AG-1749 and AG-2
25 mM phosphate buffer containing 000 (25 μl, p
H6.0) is added, and in the case of AG-1749 at 37 ° C., 60
And AG-2000 for 30 minutes. After the reaction, urea (500 mM), phenol red (0.02% by weight), dithiothreitol (0.02%) were added to each reaction solution.
50 mM phosphate buffer (100 μl, p containing 1 mM)
H7.0) was added and reacted for 60 minutes. After the reaction, the absorbance at 550 nm of each reaction solution was measured. AG-174
9 or the absorbance of the reaction solution without addition of AG-2000 to 100
%, Against which the% inhibition was calculated from the absorbance at each sample addition concentration and plotted against each sample concentration. From this plot, find the sample concentration that gives 50% inhibition,
It was defined as the 50% inhibitory concentration (IC ₅₀ ). The urease 1 unit is obtained by hydrolyzing urea to give 1 unit per minute at 25 ° C.
It is defined as the activity that produces micromolar ammonia. Test results AG-1749 and AG-2 measured by the above test method
000 of Helicobacter pyl
ori) The IC ₅₀ for urease derived from NCTC 11637 was 4.6 μM and 8.0 μM, respectively.

[0020]

INDUSTRIAL APPLICABILITY The urease inhibitor of the present invention can be used for the prevention and treatment of diseases caused by Helicobacter genus bacteria by suppressing the production of ammonia and further suppressing the growth of Ureaplasma bacteria.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location C12N 9/99 9152-4B // C07D 401/12 235

Claims (19)

[Claims] 1. A urease inhibitor derived from a genus Helicobacter or a genus Ureaplasma comprising a 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound having an anti-ulcer effect or a salt thereof. 2. A 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound having an antiulcer action is represented by the general formula: [In the formula, ring A may be substituted, R ¹ and R ³ are the same or different and each represents a hydrogen, an alkyl group or an alkoxy group, and R ² is a hydrocarbon residue which may have a substituent. The urease inhibitor according to claim 1, which is a compound represented by the formula [1]. 3. The urease inhibitor according to claim 2, wherein ring A is unsubstituted. 4. The urease inhibitor according to claim 2, wherein R ¹ is an alkyl group. 5. The urease inhibitor according to claim 2, wherein R ¹ is a methyl group. 6. The urease inhibitor according to claim 2, wherein R ³ is hydrogen. 7. The urease inhibitor according to claim 2, wherein R ³ is an alkyl group. 8. The urease inhibitor according to claim 2, wherein R ³ is a methyl group. 9. The urease inhibitor according to claim 2, wherein R ² is an optionally fluorinated alkyl group. 10. A 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound having an anti-ulcer activity is represented by the general formula: [In the formula, ring A'may be substituted, R ¹ 'and R ³ ' may be the same or different and each represents a hydrogen atom, an alkyl group or an alkoxy group, and R ² 'may have a substituent. hydrogen residue, X ^- is urease inhibitor according to claim 1, wherein the compound represented by showing anion, respectively. 11. The urease inhibitor according to claim 10, wherein the A ′ ring is unsubstituted. 12. The urease inhibitor according to claim 10, wherein R ¹ 'is an alkyl group. 13. The urease inhibitor according to claim 10, wherein R ¹ 'is a methyl group. 14. The urease inhibitor according to claim 10, wherein R ³ 'is hydrogen. 15. The urease inhibitor according to claim 10, wherein R ³ 'is an alkyl group. 16. The urease inhibitor according to claim 10, wherein R ³ 'is a methyl group. 17. The urease inhibitor according to claim 10, wherein R ² 'is an alkyl group which may be fluorinated. 18. A Helicobacter genus is Helicobacter
The urease inhibitor according to claim 1, which is pylori. 19. A ureaplasma is ureaplasma.
The urease inhibitor according to claim 1, which is urealyticum.