JPH08119862A - Bismuth complex and antibacterial agent containing the same - Google Patents

Abstract

PURPOSE: To obtain thiosalicylic acid bismuth complex and its salt having an excellent antibacterial action, especially a Helicobacter pylori-resistant action. CONSTITUTION: A bismuth compound (e.g. bismuth nitrate pentahydrate) is reacted with a mercapto group-having thiosalicyclic acid or 2-mercaptoethanol in a solvent (e.g. ethanol) at the ordinary temperature to a high temperature to obtain salicyclic acid bismuth complex or its salt, or 2-mercaptoethanol bismuth complex or its salt. Bismuth and salicyclic acid 2-mercaptoethanol are bound to each other in a ratio of 1:2, 1:3 or 2:3. The bismuth complex or its salt is added as an active ingredient to obtain the antibacterial agent. The antibacterial agent is especially useful for preventing or treating diseases caused by Helicobacter pylori. The administration amount of the active ingredient is 1-500mg per unit administration, and the active ingredient is administered in an unit administration amount of 0.25-500mg/individual body once-four times a day.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a bismuth complex, a salt thereof, and an antibacterial agent containing the bismuth complex as an active ingredient, and is used in the medical field.

[0002]

2. Description of the Related Art Helicobacter
er), especially Helicobacter pylori (Helic)
(Obter Pylori, sometimes referred to as “HP” hereinafter) is known as a pathogen of gastrointestinal tract disorders in humans and animals, and is detected at a high rate in patients with gastritis and gastric ulcer. A causal relationship with is pointed out. Bismuth compounds have been widely used as drugs for gastrointestinal catarrh and ulcers, and among them, colloidal bismuth subsiterate (CBS), which is a complex of bismuth and citric acid used as a drug for treating gastrointestinal ulcers.
And bismuth subsalicylate, which is a complex of bismuth and salicylic acid. P. It is known that it has an antibacterial activity against
s Chemother. 1985, 28, 83
7). On the other hand, a salt of a complex in which bismuth and 2-mercaptoethanol are bonded at a ratio of 1: 2 [Bi (SCH ₂
CH ₂ OH) ₂ ] · ClO ₄ is polyhedron
(Vol. 3, No 1, 71-73, 1984), but its use is not described.

[0003]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The above-mentioned bismuth complex, other antibiotics, antiulcer agents, H. P. The antibacterial activity against Helicobacter is not sufficient, and an antibacterial agent against Helicobacter genus has not yet been put to practical use.

[0004]

SUMMARY OF THE INVENTION The inventors of the present invention have
As a result of extensive studies on antibacterial agents against Helicobacter spp. P. Paying attention to the finding that urease generates alkaline ammonia by urease to neutralize gastric acid and exists in the stomach, and bismuth ion, which is known to have anti-Helicobacter pylori activity, and H. P.
The present invention has been completed by synthesizing a complex and a salt thereof to which a compound having a mercapto group (-SH group) that inhibits the activity of urease produced by Saccharomyces cerevisiae is bound and found to have excellent anti-Helicobacter pylori activity. .

The complex of bismuth and thiosalicylic acid of the present invention and salts thereof, and the complex of bismuth and 2-mercaptoethanol and salts thereof (provided that the chemical formula Bi (S
The complex represented by CH ₂ CH ₂ OH) ₂ and its salt) is new and is produced as follows.

That is, a bismuth compound (for example, bismuth nitrate pentahydrate, bismuth sulfate, bismuth chloride, bismuth fluoride, bismuth bromide, bismuth iodide, etc.) and thiosalicylic acid having a mercapto group (chemical formula 1) or 2- It is produced by reacting with mercaptoethanol (Chemical Formula 2).

Embedded image

Embedded image Preferred bismuth compounds include bismuth nitrate pentahydrate. This reaction can be carried out in a conventional solvent such as water, methanol or ethanol. The reaction temperature is not particularly limited, and the reaction is usually performed at room temperature or under heating. Depending on the acidity and basicity of the reaction solvent, the dissociation state of protons in thiosalicylic acid and 2-mercaptoethanol, and the type of counterion, bismuth and compounds having these mercapto groups are 1: 2, 1: 3,
They combine at a ratio of 2: 3 or the like to form a complex.

Further, a complex or a salt thereof bound in a certain ratio is prepared by the above method, and then the complex or a salt thereof is further reacted with a bismuth compound or a compound having a mercapto group under the above reaction conditions to give different ratios. It is also possible to prepare the complex bound by and the salt thereof. Preferred counter ions include ammonium ion, sodium ion, potassium ion, etc. as cations,
Examples of the anion include nitrate ion, sulfate ion, perchlorate ion, hydroxide ion, and halogen ion. These counter ions are liberated from the raw material bismuth compound, the reaction solvent, or a base added to the reaction solvent for adjusting the liquidity, and form a salt with the complex of the present invention. Therefore, preferred salts of the complex of the present invention include:
For example, ammonium salt, sodium salt, potassium salt,
Examples thereof include nitrates, sulfates and perchlorates. Also,
The complex and its salt of the present invention have a crystal solvent (for example, crystalline ethanol) and / or crystal water derived from the crystal water contained in the above-mentioned reaction solvent or bismuth compound, and / or when they are not coordinated. It may be coordinated, and these are all included in the scope of the present invention.

The antibacterial agent of the present invention contains a complex of bismuth and a compound having a mercapto group or a salt thereof as an active ingredient. A complex of bismuth and a compound having a mercapto group has a bismuth-thiolate bond (B
i-S-) is preferable. Examples of the compound having a mercapto group include, in addition to the above-mentioned thiosalicylic acid and 2-mercaptoethanol, for example, a compound having a mercapto group in an aromatic ring (for example, thiophenol) and a compound having a mercapto group in a heterocycle (for example, 4 -Mercaptopyridine, 2-mercaptopyrimidine, 2-mercaptoimidazole, 5-mercapto-2-methyl-1,
3,4-thiadiazole, 5-mercapto-1-methyl-1H-tetrazole and the like), alcohols having a mercapto group (2,3-dimercapto-1-propanol and the like) and the like. Therefore, the active ingredient of the antibacterial agent of the present invention is a complex of bismuth and a compound having these mercapto groups and a salt thereof. Among these complexes, a complex of bismuth and thiosalicylic acid and a complex of bismuth and 2-mercaptoethanol are preferable, and further, in the complex, the binding ratio of bismuth and thiosalicylic acid or bismuth and 2-mercaptoethanol is respectively. Particularly preferred are 1: 2, 1: 3 or 2: 3.
Examples of the salt of the complex include the above-mentioned salts. Further, in the complex of bismuth and a compound having a mercapto group used for this antibacterial agent and its salt, in addition to the above-mentioned complex, a known complex such as the chemical formula Bi (SCH ₂ CH ₂ OH) is used.
Complexes represented by ₂ and salts thereof (for example, perchlorates, nitrates, etc.), and those having crystal water or crystal solvent (for example, crystalline ethanol) are also included.

The antibacterial agent of the present invention can be applied to mammals including humans as capsules, microcapsules, tablets, granules,
It can be orally or parenterally administered in the form of a conventional pharmaceutical preparation such as powder, troche, pill, suppository, injection, suspension, syrup, etc., but oral administration is preferred. The antibacterial agent of the present invention includes, for example, sucrose, starch, mannitol,
Excipients such as sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate,
For example, cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin,
Gum arabic, polyethylene glycol, sucrose,
Binders such as starch, for example, starch, carboxymethyl cellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, disintegrants such as sodium hydrogen carbonate, calcium phosphate, calcium citrate, etc., such as magnesium stearate, aerosyl, talc, sodium lauryl sulfate, etc. Lubricants such as citric acid, menthol, glycine, and orange powder, and flavoring agents such as sodium benzoate, sodium bisulfite, methylparaben,
Preservatives such as propylparaben, stabilizers such as citric acid, sodium citrate, acetic acid, etc., suspending agents such as methylcellulose, polyvinylpyrrolidone, aluminum stearate, etc. Dispersants such as hydroxypropylmethylcellulose, eg water, etc. It can be produced by a conventional method using various organic or inorganic carriers conventionally used for formulation such as a diluent. The amount of active ingredient in the antibacterial agent is
The amount is sufficient to produce the desired therapeutic effect, for example, from about 1 mg to about 5 per oral or parenteral unit dose.
It is 00 mg. The active ingredient is usually a unit dose of 0.25
mg / individual to 500 mg / individual can be administered 1 to 4 times per day. However, the dose may be increased depending on the age, weight, condition of the patient or administration method.

[0010]

INDUSTRIAL APPLICABILITY A complex of bismuth containing a novel complex of the present invention and a compound having a mercapto group and a salt thereof have an excellent antibacterial action, particularly an antibacterial action against Helicobacter spp., Among them, Helicobacter pylori. Therefore, the antibacterial agents containing them as active ingredients are useful for the prevention or treatment of diseases caused by Helicobacter pylori. Hereinafter, the antibacterial action against Helicobacter pylori will be shown by test examples.

Test Example 1 Test compound 1. Complex of Example 1 2. Complex of Example 3 3. Bismuth subsalicylate (control) Used strain Clinical isolate of Helicobacter pylori isolated from human stomach No. 7004, 7007 Test method Measurement of MIC It was measured by the agar plate method. That is, Brucella agar (BBL) supplemented with 5% horse blood was used as a measurement medium to prepare 2-fold serial dilution plates for each drug. The inoculum size was adjusted by adding Bruceella aga with 5% horse blood.
Bacteria that have been cultured for 72 hours at 37 ° C, 10% carbon dioxide at r
Suspended in acFahrand 2.0 is Bruc
Bacterial fluid diluted 10 times with ella broth (10
⁶ cfu / ml) was stamped onto the measurement medium. 37
After culturing at ℃, 10% carbon dioxide gas for 72 hours, the presence or absence of bacterial growth is judged with the naked eye, and the minimum concentration that inhibits bacterial growth is MIC
And The results are shown in Table 1.

[Table 1]

Example 1 Example 1 (NH ₄ ) ₃ [Bi (C ₇ H ₄ O ₂ S) ₃ ] (C ₂
Synthesis of H ₅ OH) (H ₂ O) ₂ Bismuth nitrate pentahydrate (1 ..) was added to ethanol (80 ml) containing thiosalicylic acid (0.95 g, 6.2 mmol).
0 g, 2.1 mmol) results in a clear yellow solution. Concentrated aqueous ammonia (29%, 5 ml) was added to the reaction solution, and after standing for a while (10 minutes), the yellow precipitate formed was filtered and suspended again in 40 ml of ethanol, and concentrated aqueous ammonia (2 ml) was added to give a clear yellow color. Use as a solution. The reaction solution is once naturally filtered, and the filtrate is allowed to stand in a refrigerator (3 ° C.) for several days, whereby yellow hexagonal columnar crystals are precipitated. The crystals are washed with a mixed solution of methanol and diethyl ether (1: 1) 2-3 times, then with diethyl ether and air-dried to obtain a complex of bismuth and thiosalicylic acid represented by the above chemical formula. (Yield: 0.45g) IR (KBr tablet method): 3628, 3053, 1532, 1397, 1052, 102
8, 842, 804, 752,711, 652, 477, 450 cm -1 elemental _{analysis: C 23 H 34 N 3 O} 9 S 3 Bi Calculated: C: 34.45; H: 4.27 ; N: 5.24; Bi: 26.
07% analysis value: C: 34.72; H: 4.07; N: 5.28; Bi: 24.
60%

Example 2 Synthesis of [Bi ₂ (C ₇ H ₄ O ₂ S) ₃ ] Bismuth nitrate pentahydrate (1. 1.) was added to methanol (80 ml) containing thiosalicylic acid (0.95 g, 6.2 mmol).
0 g, 2.1 mmol) results in a clear yellow solution. Concentrated aqueous ammonia (29%, 1 ml) was added to the reaction solution, the resulting yellow precipitate was filtered, washed with methanol and diethyl ether in this order, and then air-dried (yield of precipitation:
0.41 g). When this precipitate was dissolved in N, N'-dimethylformamide (DMF) (30 ml) and left at room temperature, orange cubic crystals began to precipitate after a few days.
The crystals are washed with a mixed solution of DMF, methanol and diethyl ether (1: 1), and then with diethyl ether, and dried under vacuum for one week to obtain a complex of bismuth and thiosalicylic acid represented by the above chemical formula. (Yield: 0.32g) IR (KBr tablet method): 3440, 3055, 1645, 1584, 1565, 150
7, 1428, 1385, 1277, 1251, 1143, 1104, 1055, 1036,
860, 806, 747,726, 650, 557, 467, 404 cm -1 elemental _{analysis: C 21 H 12 O 6 S} 3 Bi 2 Calculated: C: 28.84; H: 1.38 ; N: 0.00; Bi: 47.
80% analytical value: C: 28.97; H: 1.56; N: 0.17; Bi: 46.
76%

Example 3 [Bi (SCH ₂ CH ₂ O
Synthesis of H) ₂ ] (NO ₃ ) (H ₂ O) 1/2 In distilled water (10 ml) bismuth nitrate pentahydrate (743 m
g, 1.53 mmol) and 2-mercaptoethanol (234 mg, 3.0 mmol) are added and stirring is continued until a completely clear yellow solution is obtained. When the reaction solution is left in a refrigerator (3 ° C.) and cooled, yellow needle crystals are precipitated on the next day. After cooling for several days, the crystals are suction filtered and filtered for 5 m.
It was quickly washed with 1 liter of cold water and dried under reduced pressure to obtain a complex of bismuth and 2-mercaptoethanol represented by the above chemical formula. (Yield: 274 mg) IR (KBr tablet method): 3400, 2921, 2871, 1763, 1624, 139
3, 1279, 1208, 1156, 1052, 1002, 934, 825, 656, 485
cm ^-1 Elemental analysis: Calculated as C ₄ H ₁₁ NO _5.5 S ₂ Bi: C: 11.06; H: 2.55; N: 3.23; Bi: 48.
12% analytical value: C: 11.14; H: 2.25; N: 3.23; Bi: 47.
85%

Example 4 [Bi (SCH ₂ CH ₂ O) (S
CH ₂ CH ₂ OH)] in ethanol (10 ml) bismuth nitrate pentahydrate (23
0 mg, 0.47 mmol) and 2-mercaptoethanol (112 mg, 1.43 mmol) are added and stirring is continued until it becomes a completely clear yellow solution. 29% in the reaction solution
Ammonia water (1 ml) was added, and after spontaneous filtration,
Leave at room temperature. After a few days, the precipitated yellow needle crystals are filtered, washed with diethyl ether, and air-dried to obtain a complex of bismuth and 2-mercaptoethanol represented by the above chemical formula. (Yield: 95 mg) IR (KBr tablet method): 3734, 3392, 2947, 2908, 2854, 281
7, 2695, 2603, 1636, 1469, 1456, 1420, 1407, 1385,
1327, 1272,1206, 1173, 1070, 1047, 1010, 942, 833,
661, 523,502, 415 cm ^-1 Elemental analysis: Calculated as C ₄ H ₉ O ₂ S ₂ Bi: C: 13.26; H: 2.50; N: 0.00; Bi: 57.
69% analysis value: C: 13.45; H: 2.39; N: 0.00; Bi: 59.
92%

Example 5 [Bi (SCH ₂ CH ₂ O
H) ₃ ] Synthesis of the complex (266) obtained in Example 4 in distilled water (15 ml)
mg, 0.38 mmol) and 2-mercaptoethanol (268 mg, 3.43 mmol) are added and stirring is continued. The undissolved precipitate is filtered off and the filtrate is left to cool in the refrigerator (3 ° C). After several days, the precipitated yellow needle crystals were filtered, washed with cold water, a mixture of methanol and diethyl ether (2: 1), diethyl ether in that order, and air-dried to obtain a mixture of bismuth represented by the chemical formula and 2-mercaptoethanol. Obtain the complex. (Yield: 110 mg) IR (KBr tablet method): 3307, 2913, 2871, 1742, 1469, 140
0, 1279, 1212,1162, 1060, 995, 834, 734, 659, 526,
478 cm ^-1 Elemental analysis: Calculated as C ₆ H ₁₅ O ₃ S ₃ Bi: C: 16.36; H: 3.43; N: 0.00; Bi: 47.
46% analysis value: C: 15.89; H: 3.13; N: 0.09; Bi: 47.
33%

Example 6 The complex of Example 3, lactose, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose were thoroughly mixed and then granulated. Then, it was vacuum dried at 40 ° C. and sized. Magnesium stearate was added to the granules and compressed to give tablets having the following ingredient contents per tablet.

[Equation 1]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Souhei 1-68-65, Numa, Yao-shi, Osaka Prefecture Asahi Plaza City Yaominami 2nd Building No. 612

Claims (9)

[Claims] 1. A complex of bismuth and thiosalicylic acid and a salt thereof. 2. Bismuth and thiosalicylic acid are 1: 2,
The complex and its salt according to claim 1, which are bound at a ratio of 1: 3 or 2: 3. 3. A complex of bismuth and 2-mercaptoethanol and a salt thereof (provided that the chemical formula Bi (SCH ₂ C
H ₂ OH) ₂ and its salts are excluded). 4. The complex and a salt thereof according to claim 3, wherein bismuth and 2-mercaptoethanol are bound in a ratio of 1: 3 or 2: 3. 5. An antibacterial agent containing a complex of bismuth and a compound having a mercapto group or a salt thereof as an active ingredient. 6. The antibacterial agent according to claim 5, wherein the compound having a mercapto group is thiosalicylic acid. 7. Bismuth and thiosalicylic acid are 1: 2,
The antibacterial agent according to claim 6, which contains a complex or a salt thereof bound in a ratio of 1: 3 or 2: 3 as an active ingredient. 8. The antibacterial agent according to claim 5, wherein the compound having a mercapto group is 2-mercaptoethanol. 9. The antibacterial agent according to claim 8, which contains a complex in which bismuth and 2-mercaptoethanol are bound at a ratio of 1: 2, 1: 3 or 2: 3 or a salt thereof as an active ingredient.