JPH10316651A - Dithiodibenzohydroxamic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide the subject new compound having excellent inhibiting action on the activity of Helicobacter pylori participating in the onset of gastrointestinal diseases such as chronic gastritis, gastric ulcer and duodenal ulcer. SOLUTION: This compound is expressed by the formula, e.g. 2,2' dithiodibenzohydroxamate. The compound of the formula can be produced by reacting aminobenzoic acid with sodium nitrite to form a diazonium salt, reacting the salt with sodium disulfide, esterifying the obtained compound with an alcohol at 0-150 deg.C in the presence of preferably 10-30 times mol of a catalyst (e.g. hydrogen chloride, concentrated sulfuric acid or phosphoric acid) and reacting the produced ester with 2-2.5 times mol of hydroxylamine at a temperature between 0 deg.C and room temperature for 1-24 hr in the presence of 1-10 times mol of a base (e.g. triethylamine or pyridine).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a helicobacter
The present invention relates to a novel dithiodibenzohydroxamic acid derivative that inhibits the activity of pyrroliurease.

[0002]

2. Description of the Related Art In recent years, it has been revealed that Helicobacter pylori urease produced by Helicobacter pylori is deeply involved in the development of gastrointestinal diseases such as chronic gastritis and gastric / duodenal ulcer. The mechanism of gastric mucosal injury caused by Helicobacter pylori urease is considered as follows.

[0003] Urea secreted from the stomach wall is hydrolyzed by Helicobacter pylori urease to produce ammonia and carbon dioxide. The ammonia has a strong mucosal damage effect, causes gastric mucosal blood flow impairment, neutralizes gastric acid, and enables Helicobacter pylori to inhabit the stomach, which is a severely acidic environment.

[0004] On the other hand, when Helicobacter pylori adheres to the gastric mucosa, the cytokine IL is released from the gastric mucosal epithelial cells.
(Interleukin) -8 is produced and such IL-8
Acts on neutrophils, causing them to migrate and activate. The activated neutrophils cause phagocytosis and phagocytic vacuoles, as well as producing active oxygen and degranulation. The active oxygen itself causes mucosal damage, and is led to hypochlorous acid by the action of chlorine and myeloperoxidase present in the stomach, and by the ammonia,
It is converted to monochloramine and is thought to cause cell damage.

[0005] Further, the above-mentioned ammonia reduces reduced glutathione, which is an active oxygen scavenger, and enhances the production of active oxygen.

[0006]

Therefore, a urease activity inhibitor that inhibits the activity of the urease produced by Helicobacter pylori has been attracting attention. Examples of such urease activity inhibitors include hydroxamic acids such as acetohydroxamic acid (A), benzohydroxamic acid (B) and nicotinohydroxamic acid (C);
Disulfides such as 2,2′-dipyridyl disulfide, cysteine, and disulfiram; hydroquinone, p
Phenols such as -nitrophenol and p-aminophenol are known.

The hydroxamic acids (A) to (C) are
Kobashi et al., Biochemical Etobiophysica Acta, 65, 380-383 (1962) (K. Kobayashi e
tal., Biochem. Biophys. Acta., 65, 380-383 (1962)) and Biochemica et Biophysica Actor, 22.
7, 429-441 (1971) (K. Kobayashi et al., I
bid, 227, 429-441 (1971)).

Further, disulfides are described in Biochemical Journal, 159, 245-257, by Norris et al.
(1976) (R. Norris et al., Biochem. J., 159, 245-25.
7 (1976)) or Journal of Biological Chemistry by Todd et al., 266, 10260-10.
267 (1991) (Matthew J. Todd, Robert P. Hausing
er, J. Biol. Chem., 266, 10260-10267 (1991)).

[0009] However, these compounds are insufficient for the above-mentioned action of inhibiting the urease activity of Helicobacter pylori. Accordingly, an object of the present invention is to provide a novel compound having an urease activity inhibitory activity, particularly an excellent inhibitory activity on Helicobacter pylori urease.

[0010]

Means for Solving the Problems The present inventors have conducted intensive studies to develop a compound effective for inhibiting urease activity, particularly for inhibiting urease activity of Helicobacter pylori, and as a result, formula (1):

[0011]

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The novel dithiodibenzohydroxamic acid derivative (1) represented by the formula (1) or a pharmaceutically acceptable salt thereof has a novel urease activity inhibitory activity which is much stronger than that of a conventional compound having an urease activity inhibitory activity. They found the facts and completed the present invention. That is, since the dithiodibenzohydroxamic acid derivative (1) of the present invention has, in the same molecule, the hydroxyme group of hydroxamic acids and the disulfide group of disulfides having an urease activity inhibitory activity, each of these functional groups has The synergistic inhibitory effect of urease activity is exhibited by the simultaneous or stepwise expression of the inhibitory power.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The dithiodibenzohydroxamic acid derivative of the present invention can be produced by the following production method. In the following reaction scheme, examples of the lower alkyl group include lower alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, and hexyl.

Examples of the halogen atom include fluorine, chlorine, bromine and iodine. Reaction Scheme I

[0015]

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This reaction is carried out by subjecting the compound represented by the general formula (3) to a usual esterification reaction to obtain an ester of the compound (2), and then reacting with hydroxylamine in the presence of a base. The compound of the present invention represented by the general formula (1) is obtained. The above esterification reaction is carried out, for example, by reacting compound (3) with an alcohol represented by the general formula: R ¹ —OH (wherein R ¹ represents a lower alkyl group) in the presence of a catalyst. Done. As a catalyst to be used, a catalyst commonly used for an esterification reaction is used, and specifically, inorganic acids such as hydrogen chloride, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, perchloric acid, and trifluoroacetic acid Organic acids such as trichloromethanesulfonic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid and ethanesulfonic acid, acid anhydrides such as trichloromethanesulfonic anhydride and trifluoromethanesulfonic anhydride, and thionyl chloride Catalyst. Further, a cation exchange resin (acid type) can also be used.

The above esterification reaction is carried out without a solvent or in the presence of a suitable solvent. As the solvent used, any of the solvents commonly used in esterification reactions can be used,
For example, aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; and ethers such as diethyl ether, tetrahydrofuran, and dioxane.

The use ratio of the acid to the compound (3) is preferably equimolar to 100-fold molar amount, more preferably 10 to 30-fold molar amount. Further, the reaction temperature is -20 ° C to 200 ° C.
C., preferably from 0 to 150.degree. Also,
Compound (2) is prepared by adding an alkali metal salt (eg, sodium salt, potassium salt, etc.) of compound (3) to a compound represented by the general formula: R ¹ -X (wherein X represents a halogen atom. R ¹ is the same as described above) ), A method of reacting compound (3) with diazoalkanes such as diazomethane, diazoethane, diazopropane, etc., and a method of converting a carboxy group of compound (3) into a reactive group (acid chloride). Amide or anhydride) and then reacting with an alcohol represented by the general formula: R ¹ —OH (wherein R ¹ is the same as described above). These esterification reactions can be performed according to a conventional method.

Examples of the solvent used in the reaction for obtaining (1) from (2) include alcohols such as methanol and ethanol, and ethers such as dimethyl ether, diethyl ether, tetrahydrofuran and dioxane.
Examples of the base include trialkylamines such as triethylamine and tributylamine, pyridine, picoline, 1,5-diazabicyclo [4.3.0] nonene-
5,1,4-diazabicyclo [2.2.2] octane,
1,8-diazabicyclo [5.4.0] undecene-7
Inorganic bases such as alkali metal hydroxides such as sodium hydroxide and potassium carbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. Is raised.

These bases are added to the compound (2) by 1
It is suitable to use it in a molar amount of 20 to 20 times, preferably 1 to 10 times. The reaction may be carried out at 0 to 150 ° C, preferably at 0 ° C to room temperature for about 1 to 24 hours. Also,
The use ratio of hydroxylamine to the compound (2) is at least 2 times, preferably 2 to 2.5 times the molar amount. The reaction is usually performed at 0 ° C. to room temperature. Reaction process formula II

[0021]

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In this reaction, the compound of formula (3) and hydroxylamine are reacted with N, N 'without solvent or in a suitable solvent.
The compound represented by the general formula (1) of the present invention is obtained by using a condensing agent such as -dicyclohexylcarbodiimide (DCC). At this time, if a tertiary amine is added, the basicity of the hydroxylamine is improved, so that the reaction is accelerated.

In place of DCC, it is possible to use a condensing agent such as isobutyl chloroformate, diphenylphosphinic chloride and the like. Solvents used include tetrahydrofuran (THF),
Examples thereof include N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene chloride, and chloroform.

Examples of the tertiary amine include triethylamine, tributylamine, pyridine, pyrimidine, morpholine, lutidine and the like. The use ratio of N, N'-dicyclohexylcarbodiimide (DCC) to compound (3) is at least twice the molar amount,
Preferably, it is used in a 2- to 2.5-fold molar amount.

The use ratio of hydroxylamine to compound (3) is the same as in the above-mentioned reaction step formula I.
The reaction is usually performed at -10 ° C to room temperature, and
It ends in about an hour. Reaction scheme III In order to obtain the compound (3) as a starting material of the reaction scheme I, various methods shown in the following reaction schemes (i) to (v) can be exemplified.

[0026]

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(In each formula, R is a group:

[0028]

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Is shown. Ph represents a phenyl group;
X is the same as above. The reaction represented by the reaction formula (i) is carried out by reacting a halide with sodium thiosulfate to obtain a thiosulfate and then reacting with thiol benzoate to obtain a compound (3).
Is what you get. In the reaction of the reaction formula (ii), a diazonium salt is obtained by reacting aminobenzoic acid with sodium nitrite, and then a compound (3) is obtained by reacting sodium disulfide.

In the reaction of the reaction formula (iii), a compound (3) is obtained by oxidatively coupling two molecules of thiol benzoate with dimethyl sulfoxide. In the reaction of the reaction formula (iv), thionitrate is obtained by using nitrogen dioxide on thiol benzoate, and then another thiol or dibenzoamine is reacted to obtain a compound (3).

In the reaction of the reaction formula (v), a compound (3) is obtained by a coupling reaction using a sulfenyl halide in the presence of a catalytic amount of tetrakistriphenylphosphine palladium and tetramethyltin. Of the above reaction formulas (i) to (v), considering the safety of the reagents used, the ease of handling, and the ease of separation of the product (3) from other compounds, the reaction formula (ii) It is preferable to synthesize compound (2) based on this.

The sodium nitrite used in the reaction formula (ii) is used at least in an equimolar amount, preferably 1 to 1.5 times in molar ratio, with respect to the compound (5-b). It is. The sodium disulfide used is at least 0.5-fold the molar amount of the compound (5-b),
Preferably, it is used in a molar amount of 1 to 1.5 times. The reaction may be performed at -10 ° C to room temperature, preferably at 0 ° C to room temperature for about 2 to 5 hours.

The above dithiodibenzohydroxamic acid derivative (1) includes an addition salt of a pharmaceutically acceptable acid or base compound. The salt is easily formed by reacting the following acid or base. Examples of the acid used for salt formation include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and in some cases, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid. And other organic acids.

The base used for salt formation includes, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like. The dithiodibenzohydroxamic acid derivative of the present invention is usually used in the form of a general pharmaceutical preparation. The formulations are prepared using commonly used diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and lubricants.

Various forms can be selected as the pharmaceutical preparation according to the purpose of treatment. Representative examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules,
Suppositories, injections, (solutions, suspensions, etc.), ointments and the like can be mentioned. When molded into a tablet form, carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and other excipients, water, ethanol, propanol, Syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, calcium phosphate, polyvinylpyrrolidone and other binders, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan Disintegrating agents such as fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch and lactose; disintegrating inhibitors such as sucrose, stearin, cocoa butter and hydrogenated oil;
Absorption enhancers such as quaternary ammonium salts and sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearates, boric acid powder, polyethylene Lubricants such as glycol can be used. Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-enclosed tablets, intestinal juice-coated tablets, film-coated tablets or double tablets or multilayer tablets.

When molded into a pill form, the carrier may be, for example, an excipient such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, tragacanth powder, gelatin, ethyl alcohol or the like. Disintegrants such as binders, laminaran, agar, and the like can be used. For molding into a suppository form, for example, polyethylene glycol, cocoa butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like can be used as carriers.

The capsules are prepared according to a conventional method, usually by mixing the above-mentioned various carriers and the dithiodibenzohydroxamic acid derivative of the present invention or a pharmaceutically acceptable salt thereof, into hard gelatin capsules, hard capsules and the like. It is done by filling. When prepared as an injection, the solutions, emulsions and suspensions are preferably sterile and isotonic with blood. In molding into these forms, for example, water, lactic acid aqueous solution, ethyl alcohol, propylene glycol, ethoxylated isostearin alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used as diluents. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and ordinary solubilizing agents, buffers, soothing agents and the like may be added. May be. further,
If necessary, coloring agents, preservatives, flavors, flavors, sweeteners, and other pharmaceuticals may be included in the pharmaceutical preparation.

In the preparation of pastes, creams and gels, diluents such as white petrolatum,
Paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicon, bentonite and the like can be used. The amount of the dithiodibenzohydroxamic acid derivative of the present invention or a pharmaceutically acceptable salt thereof is not particularly limited and is appropriately selected from a wide range.
The content is preferably 70% by weight.

The method of administration of the dithiodibenzohydroxamic acid derivative of the present invention is not particularly limited, and is variously determined according to the age, sex and other conditions of the patient, disease state, etc., and various preparation forms. It is administered orally or parenterally, either topically or topically. For example, it is orally administered in the form of tablets, pills, solutions, suspensions, emulsions, granules and capsules, and in the form of injections, mixed with usual replenishers as needed, for intravenous, intramuscular, or intradermal use. It is administered internally, subcutaneously or intraperitoneally, rectally as a suppository, or as an ointment.

The dose of the dithiodibenzohydroxamic acid derivative of the present invention to humans is appropriately selected depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time and the like.
Usually 0.1-100mg / kg body weight per day
Is administered in one or several divided doses. Further, the dithiodibenzohydroxamic acid derivative (1) of the present invention may be used alone, or may have other pharmacological activity, for example, an antibiotic such as amoxicillin or clarithromycin; a nitronid such as metronidazole or tinidazole. Zole-based insecticides; Bismuth preparations, antiulcer agents such as sofacolcon and pronotol; Propump inhibitors such as omeprazole and lansoprazole may be used in combination, and can remove Helicobacter pylori with a high probability. It can cure gastrointestinal diseases such as chronic gastritis and gastric / duodenal ulcer.

[0041]

The present invention will now be described in detail with reference to Reference Examples and Examples. Reference Example 1 [Synthesis of diethyl 2,2'-dithiodibenzoate]
Sodium sulfide (39 g, 0.15 mol) and sulfur (4.
(8 g, 0.15 mol) in distilled water (80 ml), and the reaction mixture was heated at 100 ° C. 30
A minute later, a 7.5N aqueous sodium hydroxide solution was added to the mixture, and the mixture was cooled to 0 ° C. to obtain sodium disulfide.

Next, a 6N aqueous hydrochloric acid solution (180 m
To 1), 2-aminobenzoic acid (13.7 g, 0.10 mol) was added, and the mixture was stirred and cooled to about 5 ° C. Then, sodium nitrite (10.4 g, 0.15 mol) dissolved in 45 ml of water was gradually added to the mixture, and the mixture was stirred at room temperature. After about 30 minutes, the 2-aminobenzoic acid was completely dissolved and the color of the mixture became light brown, forming a diazonium salt.

Then, at 0 ° C., a diazonium salt solution was slowly added to the sodium disulfide solution. After the addition was completed, the mixture was heated to room temperature and stirred for 3 hours. Then, 6N hydrochloric acid (40 ml) was added to the mixture, the deposited precipitate was filtered, and the filtrate was washed with water.
Then, the filtrate was washed with a 3N aqueous sodium hydroxide solution (1
00 ml) and washed with ethyl acetate (500 ml). The aqueous layer was acidified with 6N hydrochloric acid (50 ml), and the deposited precipitate was filtered, washed with water, and dried in a desiccator to obtain dithiodibenzoic acid.

Further, after the above unpurified dithiodibenzoic acid was dissolved in a mixed solution of sulfuric acid (10 ml) and anhydrous ethanol (100 ml), the reaction solution was heated to 100 ° C. After 12 hours, the reaction solution was cooled to room temperature, neutralized with a saturated aqueous solution of sodium carbonate, and extracted three times with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel chromatography (silica gel: manufactured by Wako Pure Chemical Industries, eluent: chloroform: hexane = 1: 2).
And then recrystallized from ethanol to obtain the title compound (8.26 g, total yield 4).
5.6%). Melting point: 101-104 ° C ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.4
5 (t, J = 7.2 Hz, 3H), 4.46 (q, J =
7.2 Hz, 2H), 7.24 (ddd, J = 1.6,
7.4, 8.2 Hz, 2H), 7.41 (ddd, J =
1.1, 7.4, 7.6 Hz, 2H), 7.76 (d
d, J = 1.1, 8.2 Hz, 2H), 8.08 (d
d, J = 1.6, 7.6 Hz, 2H) ¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 14.
3, 61.5, 125.6, 125.9, 127.7,
131.4, 133.0, 140.4, 166.6 FT-IR (KBr): 2982, 1699, 145
9, 1270 cm ^-1 EI-MS m / z (relative intensity%): 362 (M ⁺ ,
36), 153 (100), 181 (69), 136
(41) The elemental analysis values are as follows. Calculated value (%): C, 59.7; H, 5.0. Found (%): C, 59.7; H, 5.0. Reference Example 2 [Synthesis of diethyl 3,3'-dithiodibenzoate]
The reaction was carried out in the same manner as in Reference Example 1 except that the same molar amount of 3-aminobenzoic acid was used instead of 2-aminobenzoic acid, followed by silica gel chromatography (silica gel: supra, eluent: ethyl acetate: hexane = 1:20) to give the title compound as an oil (total yield 70.7%).

¹ H-NMR (300 MHz, CDC
l ₃ ) δ: 1.38 (t, J = 7.2 Hz, 3H),
4.37 (q, J = 7.2 Hz, 2H), 7.41
(T, J = 7.7 Hz, 2H), 7.69 (dd, J =
1.1, 7.7 Hz, 2H), 7.90 (dd, J =
1.1, 7.7 Hz, 2H), 8.17 (t, J = 1.
1 Hz, 2H) ¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 14.
2, 61.2, 128.6, 128.8, 129.2,
131.8, 134.6, 137.4, 165.8. FT-IR (KBr): 2982, 1721, 141
8, 1260 cm ^-1 . FAB-MS (glycerol) m / z: 363 (MH
⁺ ). Reference Example 3 [Synthesis of diethyl 4,4'-dithiodibenzoate]
The reaction was carried out in the same manner as in Reference Example 1 except that 4-aminobenzoic acid was used in the same molar amount instead of 2-aminobenzoic acid, followed by silica gel chromatography (silica gel: supra, eluent: ethyl acetate: benzene: Hexane = 1:
1:50) to give the title compound as an oil (total yield 70.9%).

¹ H-NMR (300 MHz, CDC
l ₃ ) δ: 1.38 (t, J = 7.2 Hz, 3H),
4.36 (q, J = 7.2 Hz, 2H), 7.45
7.60 (m, 2H × 2), 7.95 to 8.00 (m,
2H × 2) ¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 14.
2, 61.1, 126.0, 129.0, 130.3,
142.0, 166.0 FT-IR (KBr): 2982, 1721, 141
8, 1260 cm ^-1 EI-MS m / z (relative intensity%): 362 (M ⁺ ,
100), 137 (72), 136 (34), 182
(32). Example 1 [Synthesis of 2,2'-dithiodibenzohydroxamate]
To a 0.1 N aqueous sodium hydroxide solution (10 ml) was added hydroxylamine hydrochloride (2.1 g, 30.22) at room temperature.
Mmol) and stirred to dissolve completely. To the resulting reaction solution, a solution of diethyl 2,2′-dithiodibenzoate (1.07 g, 2.95 mmol) in 1,4-dioxane (30 ml) was added at room temperature while stirring.
After slowly adding over 5 minutes, the mixture was stirred for 36 hours. After completion of the reaction, the reaction solution was acidified with 3N hydrochloric acid at 0 ° C., and extracted three times with chloroform. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.

The obtained residue was recrystallized from chloroform to give the title compound. Melting point: 142-145 ° C ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.4
5 (ddd, J = 2.7, 5.5, 8.0 Hz, 2
H), 7.60-7.72 (m, 2H x 2), 8.08
(Dt, J = 0.9, 8.0 Hz, 2H) ¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 120.
8, 124.3, 125.3, 126.0, 131.
7, 144.9, 169.2 FT-IR (KBr): 3058, 2912, 268
8, 1638, 1433 cm ^-1 FAB-MS (glycerol + methanol) m / z: 3
37 (MH ⁺ ) Example 2 [Synthesis of 3,3′-dithiodibenzohydroxamate]
The reaction was carried out in the same manner as in Example 1 except that diethyl 3,3'-dithiodibenzoate was used in the same molar amount instead of diethyl 2,2'-dithiodibenzoate, and the reaction was carried out at 50%
The title compound was obtained by recrystallization from ethanol. Melting point: 175-177 ° C. ¹ H-NMR (300 MHz, CD ₃ OD) δ: 7.4
3 (t, J = 7.8 Hz, 2H), 7.61 (m, 2
H), 7.69 (m, 2H), 7.92 (dd, J =
1.7 Hz, 2H) ¹³ C-NMR (75 MHz, CD ₃ OD) δ: 127.
3, 127.5, 130.8, 131.8, 135.
0, 138.9, 167.3 FT-IR (KBr): 3311, 3058, 282
3, 1619, 1467 cm ^-1 FAB-MS (glycerol + methanol) m / z: 3
37 (MH ^<+> ) Example 3 [Synthesis of 4,4'-dithiodibenzohydroxamate]
The reaction was carried out in the same manner as in Example 1 except that diethyl 4,4'-dithiodibenzoate was used in the same molar amount instead of diethyl 2,2'-dithiodibenzoate, and the reaction was carried out at 50%
The title compound was obtained by recrystallization from ethanol. Melting point: 175-177 ° C. ¹ H-NMR (300 MHz, CD ₃ OD) δ: 7.2
6 to 7.40 (m, 2H × 2), 7.52 to 7.64
(M, 2H × 2) ¹³ C-NMR (75 MHz, CD ₃ OD) δ: 128.
8, 129.3, 130.0, 139.4, 167.9 FT-IR (KBr): 3287, 3068, 274
2,1648,1438 cm ^-1 FAB-MS (glycerol + methanol) m / z: 3
37 (MH ⁺ ) The following urease activity inhibition tests were performed on the compounds obtained in Examples 1 to 3 and evaluated. In Table 1, acetohydroxamic acid (A) was used as Comparative Example 1, benzohydroxamic acid (B) was used as Comparative Example 2, and nicotinohydroxamic acid (C) was used as Comparative Example 3.

Since it is difficult to directly observe the inhibition of urease activity, ¹³ C-urea was used as the urea substrate, and the time-dependent change of urea disappeared by the urease enzyme reaction was measured by ¹³ C-NMR. Tracked. ( ^13C -NMR apparatus and measurement conditions) Apparatus: GEMINI300 (75MH, manufactured by Varian)
z) Acquisition time: 1.0 seconds Pulse decay time: 0.5 seconds Number of scans: 8 to 30 times Probe temperature: 20 ° C Spectral width: 1812.9 Hz Data points: 36192 Pulse angle: 27 ° (sample sample adjustment) In a 5 mm diameter NMR tube, 400 μl of 0.07 M phosphate buffer (pH 6.
5) Add dissolved Helicobacter pyloriurease (Otsuka Pharmaceutical Co., Ltd., 1.6 units) to 100 μl
1 to 3 or Comparative Example 1 dissolved in 1 l of ethanol
After adding the test compounds of Nos. 3 to 3, the mixture was allowed to stand at 20 ° C for 30 minutes, and then left on an ice bath for 10 minutes.

Then, 0 ° C. was separately added to the NMR tube.
¹³ C-urea (1 mg, 99 atom% ¹³ C, manufactured by Mass Trace Co.) dissolved in 100 μl of a 0.07 M phosphate buffer (pH 6.5), which had been cooled, was added to the reaction solution, and the mixture was rapidly shaken. Samples with a volume of 600 μl were prepared. A sample containing no test compound was used as a control.

The concentrations of the compounds of Examples 1 to 3 were 4.0.
95 × 10 ⁻⁶ M, the concentration of the compound (A) of Comparative Example 1 was 1.
11 × 10 ⁻⁴ M, the concentration of the compound (B) of Comparative Example 2 was 1.
22 × 10 ⁻⁵ M, the concentration of the compound (C) of Comparative Example 3 was 1.
It was 21 × 10 ⁻⁵ M. (Measurement method) The sample was inserted into a probe, an enzyme reaction was performed at a reaction temperature (probe temperature) of 20 ° C., and 1 minute to 4 minutes after the start of the reaction, every 20 seconds, and 1 minute after 4 minutes.
The measurement was performed every minute using a ¹³ C-NMR apparatus.

Under the above conditions, the substrate ¹³ C-
Simultaneously with loss of signal 165ppm of urea, the ¹³ C- urea hydrolyzed by urease to produce ¹³
The increase in signal of 163 ppm of ¹³ C-carbonate from C-carbon dioxide was measured over time. (Evaluation method of urease inhibitory power) Evaluation was made based on the concentration (I _v50 ) of the test compound which halved the reaction rate when the test compound was not added (control). I _v50 is determined according to the following method.

Under the above-mentioned measurement conditions, the concentrations of the test compounds of Reference Examples 1 to 3 were changed using a ¹³ C-NMR apparatus, and the disappearance rate of ¹³ C-urea of the test compound at each concentration was calculated. Then, as divided by the elimination rate of ¹³ C- urea control rate of disappearance of the ¹³ C- urea, it was plotted the relationship between the concentration of the test compound, the linear expression shown in FIG. 1 was obtained.

This relationship is:

[0054]

(Equation 1)

[0055] y = ¹³ in the concentration (M) T _CONT = control ⁽¹³ C- urea elimination rate of the presence of the elimination rate / test compound of ¹³ C- urea in control) [a] = test compound C -Disappearance time (min) of urea signal T _i = representation time (min) of ¹³ C-urea signal in the presence of the test compound, expressed as a linear relationship to the concentration [I] of the test compound Is done.

Incidentally, the above I _v50 corresponds to [I] when the value of y becomes 2 in the equation (2). Therefore, y =
By substituting 2 into Equation (2), Equation (3) is derived, and I _v50 can be obtained. I _v50 of the test compounds of Examples 1 to 3 and Comparative Examples 1 to 3 were calculated, and the results are shown in Table 1.

[0057]

[Table 1]

As is clear from the results in Table 1, Comparative Example 1
It was found that the compounds of Examples 1 to 3 had lower _Iv50 against Helicobacter pylori urease than the compounds of Examples 1 to 3.

[0059]

Industrial Applicability The dithiodibenzohydroxamic acid derivative of the present invention has an excellent activity inhibitory activity against urease of Helicobacter pylori. Therefore,
The dithiodibenzohydroxamic acid derivative of the present invention is suitable for treating gastrointestinal diseases such as chronic gastritis and gastric / duodenal ulcer caused by urease of Helicobacter pylori.

[Brief description of the drawings]

FIG. 1. Concentration of test compound and ¹³
Rate of disappearance of C-urea / ^{13C in} the presence of the test compound
-It is a graph which shows the relationship with the disappearance rate of urea.

Claims (1)

[Claims] (1) Formula (1): A dithiodibenzohydroxamic acid derivative represented by the formula: or a pharmaceutically acceptable salt thereof.