KR0144442B1 - Water soluble bithmuth compound and process of preparation forthereof - Google Patents

Abstract

The present invention relates to novel water-soluble bismuth compounds of the general formula (I) below which are useful for treating ulcers.

Wherein M ₂ represents BiO, M ₁ and M ₃ are each selected from Na, K and NH ₄ , or when M ₂ is selected from Na, K and NH ₄ , one of M ₁ and M ₃ Is BiO and is selected from the other Na, K and NH ₄ .

Description

Water soluble bismuth compound and method for producing same

FIG. 1a is a C ¹³ NMR spectrum of disodium oxybismuthyl citrate. FIG.

Figure 1b is the IR spectrum of disodium oxybismuthyl citrate.

Figure 2a is a C ¹³ NMR spectrum of disodium oxybismuthyl citrate.

Figure 2b is an IR spectrum of disodium oxybismuthyl citrate.

Figure 3a is a C ¹³ NMR spectrum of diammonium oxybismuthyl citrate.

3b is the IR spectrum of diammonium oxybismuthyl citrate.

The present invention relates to novel water soluble bismuth compounds and methods for their preparation. More specifically, the present invention relates to novel water-soluble bismuth compounds represented by the following general formula (I) and useful for the treatment of ulcers and methods for their preparation.

Wherein M ₁ and M ₂ are selected from Na, K and NH ₄ and may be the same or different, respectively.

Bismuth compounds are widely known as therapeutic drugs for gastric and duodenal ulcers and are usually administered orally in the form of tablets or solutions. Orally administered bismuth compounds are gasified by gastric acid in the gastrointestinal tract to produce bismuth ions, which are known to protect the ulcer site from attack by gastric acid by binding to proteins of ulcer tissue to form a protective film. Has been found to have a fairly strong antimicrobial effect against gastrointestinal bacteria called Helicobacter pylori, which is known to cause a direct onset or relapse of various gastrointestinal diseases such as gastritis, gastric ulcer, duodenal ulcer, gastric cancer, and the like.

Among various bismuth compounds, conventional drugs used for the treatment of ulcers are listed as follows. Examples include bismuth citrate, bismuth subsalycilate, bismuth subcarbonate, bismuth subgallate, bismuth subcitrate, and the like. Among the aforementioned drugs, bismuth citrate, bismuth subsalicylate, bismuth subgallate, bismuth subcarbonate, and the like have very low water solubility, and are currently rarely used or very limitedly used for the treatment of ulcers. As a relatively recently developed water soluble drug, bismuth subcitrate is currently most commonly used. However, this bismuth subcitrate also has some disadvantages. First of all, the exact chemical structure is not known, only to the extent that it is in the form of a mixture of several compounds with complex chemical structures. Because of this, it is difficult to accurately determine the mechanism of action, it is difficult to predict the effects or side effects that can occur when combined administration with other drugs, or oral administration with a mixed composition, there is also a limit to the development of new derivatives thereof. In addition, the bismuth subcitrate is difficult to be stored for a long time due to its hygroscopicity, and has a disadvantage in that it is stable only in an ammonia solution having a pH of 9 to 11 in an aqueous state.

The present inventors have found that when bismuth subcitrate is dissolved in an alkaline solution other than an ammonia solution, such as a hydroxide or carbonate solution of an alkali metal, its stability is lowered and a large amount of precipitate is produced. In general, however, ammonia is highly volatile and it is difficult to maintain a constant pH of the solution for a long period of time, and it is particularly unpleasant to the patient due to the irritating smell and taste of ammonia when the solution is administered in liquid form. This, in turn, indicates that the use of this bismuth subcitrate, in particular as a liquid, is limited.

The present inventors have begun researching a new bismuth compound to supplement the above-mentioned disadvantages of the conventional drugs, and as a result of long-term intensive studies, the present inventors have developed a new water-soluble bismuth compound that solves the above-described disadvantages of the conventional drugs.

It is an object of the present invention to provide a new bismuth compound of the general formula (I) having a relatively simple chemical structure and excellent water solubility, in particular a bismuth compound useful for use as a liquid formulation.

Wherein M ₁ and M ₂ are selected from Na, K and NH ₄ and may be the same or different, respectively.

Preferred compounds of the present invention include the following.

Disodium oxybismuthyl citrate,

Dipotassium oxybismuthyl citrate,

Diammonium oxybismuthyl citrate,

Potassium sodium oxybismuthyl citrate,

Ammonium sodium oxybismuthyl citrate,

Ammonium potassium oxybismuthyl citrate.

In addition, the present invention is about 2 to 5 times the volume of bismuth citrate represented by the following structural formula (II) known to be excellent in treating ulcers, although its solubility in water is about 0.2% (w / v). After dispersing in, at least one compound selected from hydroxides of alkali metals, carbonates of alkali metals, and carbonates of ammonia was quantitatively added in a water solvent to react for 2 to 10 hours to prepare a transparent solution, and the solution was dried. It relates to a method for producing the water-soluble bismuth compound of the general formula (I) described above.

Conventionally, the bismuth citrate was dissolved in ammonia water and administered orally, but is not currently used due to the irritating smell of ammonia. Since the most useful solvent of this bismuth citrene is ammonia water, most of the bismuth citrate water-soluble derivatives known to date are those obtained in the aqueous ammonia solution of bismuth citrate, and the representative one is bismuth subcitrate. However, in this case, the disadvantages as described above appear by using ammonia water. The chemical structure of bismuth citrate is a structure in which Bi ³⁺ ions are bonded to three carboxyl groups of citric acid, as can be seen from the above formula (II). Accordingly, the present inventors have repeatedly attempted direct reaction bonds with alkali metal and ammonium ions, which are useful for producing water-soluble salts, of two carboxyl groups of the three carboxyl groups possessed by citric acid under pure water solvents. As a result, surprising results have been obtained that the derivatives of the new bismuth citrate of the general formula (I) having a solubility in water of at least 50% (w / v) can be obtained in almost 100% yield.

Infrared absorption spectra of the compounds of interest of the present invention exhibit absorption spectra that are almost similar to bismuth citrate, which is the starting material. However, only when the ammonium ion is bonded, a strong absorption spectrum of the NH bond appears at a wavelength around 3300 cm ^-1 .

Alkali metal and ammonium salt which can be used in the manufacturing method of this invention mentioned above are sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, ammonium hydrogen carbonate, etc. Among these, sodium carbonate, potassium carbonate, ammonium carbonate, and the like, are added in a molar ratio of 1: 1 to bismuth citrate, and sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, ammonium bicarbonate, and the like. Is introduced in a molar ratio of 1: 2. In other words, it is added in an equivalent ratio of 1: 2.

The alkali metal ammonium salts may be used alone or in combination of two or more kinds, but in order to precisely control the pH of the reaction solution, it is preferable not to use strong alkalis such as sodium hydroxide and potassium hydroxide alone, and weak alkalis and weaker ones. More preferably, the alkali and the weakest alkali salts are added in this order. For example, it is preferable to add sodium hydroxide, sodium carbonate, and sodium hydrogen carbonate sequentially. Of course, only weak alkalis can be used alone, but the reaction time is rather long.

As for reaction temperature in this invention, 0-30 degreeC is preferable, More preferably, it is 0-10 degreeC. Warming reactions above 30 ° C produced byproducts of unknown structure.

In the above production method, the final pH of the reaction solution is 6-8, preferably in the neutral range of 6.5-7.5. Outside this range, precipitates begin to form, and the more out of the range, the acid or monolithic, the more the precipitate is promoted. The final solution prepared by the above production method is colorless and odorless, and the solution of ammonium salt prepared using ammonium hydrogen carbonate or the like is also colorless and odorless. Therefore, this reaction solution can be diluted orally and orally administered. However, when the inventors compared the reaction solution and the dried powder in water for a long time under the same conditions to compare the stability of the solution, as a result of the solution of the dried powder, almost no precipitate was produced, but the reaction solution from the beginning Traces of precipitate began to form, increasing in small increments. This indicates that the reaction solution is in an unstable state.

As the drying method of the present invention, any of general high temperature concentrated drying method, spray drying method, freeze drying method and the like can be used. However, preference is given to spray drying and freeze drying methods, particularly preferred to freeze drying methods. The high temperature concentrated drying method of concentrating at high temperature for a long time may be avoided because of the possibility of byproduct formation as described above. Similarly, for a relatively short time but for the reasons mentioned above, it is also preferable to avoid the spray drying method which is usually dried at a high temperature of 150 ° C or higher. In the present invention, a method of vacuum freeze drying was used under the condition that the cooling chamber temperature is -40 ° C. Until now, an example of using a freeze drying method in the preparation of a bismuth compound is not known. The preparation method using the freeze drying method was able to obtain pure target compounds having a solubility in water of at least 50% (w / v) and in the form of a white powder in a yield of almost 100%.

The bismuth compounds of the present invention can be used in the form of general oral preparations. Such oral preparations include tablets, capsules, and liquid solutions. Solid preparations, such as tablets and capsules, may be prepared using excipients, lubricants, binders, and the like, which are generally used in at least one or more of the above compounds, and the solvent solution may include water, which is a diluent, as appropriate sweeteners, fragrances, preservatives, colorants, and the like. It can be prepared using.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the scope of the present invention is not limited by these examples.

Example 1

Preparation of Disodium Oxybismuthyl Citrate

After dispersing 39.8 g of bismuth citrate in 100 ml of purified water, a solution of 6.0 g of sodium hydroxide (99% purity) in 30 ml of purified water was slowly added dropwise over 30 minutes while maintaining the reaction temperature at about 5 ° C. After completion of the dropwise addition, the solution was stirred for 1 hour and a solution of 2.6 g of sodium carbonate dissolved in 10 ml of purified water was added dropwise for about 10 minutes. After completion of the dropwise addition, the mixture was stirred for about 1 hour, and then a 10% (w / v) sodium bicarbonate solution was slowly added dropwise until the reaction solution became clear. At this time, the pH of the reaction solution was maintained at 6.5 ~ 7.5. After completion of the dropwise addition, the mixture was stirred for 2 hours, filtered, and then freeze-dried under the condition that the cooling chamber temperature was -40 ° C to obtain 46.4 g of the title compound. The C ¹³ NMR and IR spectra of this compound are shown in FIGS. 1a and 1b, respectively.

Elemental Analysis (C ₆ H ₅ O ₈ Na ₂ Bi)

Theoretical Values: C: 15.65, H: 1.08, O: 27.82, Bi: 45.4, Na: 10.0

Measured value: C: 15.12, H: 1.11, O: 27.24, Bi: 44.9, Na: 9.8

Example 2

Preparation of Dipotassium Oxybismuthyl Citrate

49.3 g of the title compound was obtained by the same method as the Example 1, except that the following ingredients were used in the amounts described. The C ¹³ NMR and IR spectra of this compound are shown in FIGS. 2a and 2b, respectively.

Bismuth Citrate 39.8g

8.4 g potassium hydroxide (95%)

Potassium Carbonate 3.45g

0.3-0.5 g sodium bicarbonate

Elemental Analysis (C ₆ H ₅ O ₈ K ₂ Bi)

Theoretical Values: C: 14.63, H: 1.01, O: 26.00, Bi: 42.5, K: 15.9

Measured value: C: 14.37, H: 1.06, O: 26.33, Bi: 41.8, K: 15.7

Example 3

Preparation of Diammonium Oxybismuthyl Citrate

44.9 g of the title compound was obtained by the same method as the Example 1, except that the following ingredients were used in the amounts described. The C ¹³ NMR and IR spectra of this compound are shown in FIGS. 3a and 3b, respectively.

Bismuth Citrate 39.8g

Ammonium bicarbonate (99%) 15.9g

Elemental Analysis (C ₆ H ₁₃ O ₈ N ₂ Bi)

Theoretical Values: C: 16.0, H: 2.89, O: 28.44, N: 6.22, Bi: 46.4

Measured value: C: 15.7, H: 2.65, O: 28.74, N: 6.09, Bi: 46.0

Example 4

Preparation of Potassium Sodium Oxybismuthyl Citrate

47.0 g of the title compound was obtained by the same method as the Example 1, except that the following ingredients were used in the amounts described.

Bismuth Citrate 39.8g

4.0 g of sodium hydroxide (99%)

Potassium Carbonate 6.9g

Sodium hydrogen carbonate 0.1-0.3 g

0.1 to 0.3 g potassium hydrogen carbonate

Elemental Analysis (C ₆ H ₅ O ₈ NaKBi)

Theoretical Values: C: 15.12, H: 1.05, O: 26.89, Bi: 43.9, Na: 4.8, K: 8.2

Measured value: C: 14.88, H: 1.03, O: 25.36, Bi: 43.2, Na: 4.4, K: 8.4

Example 5 Preparation of Ammonium Sodium Oxybismuthyl Citrate

45.7 g of the title compound was obtained by the same method as Example 1, except that the following ingredients were used in the amounts described.

Bismuth Citrate 39.8g

4.0 g of sodium hydroxide (99%)

8.0 g ammonium bicarbonate (99%)

Elemental Analysis (C ₆ H ₉ O ₈ NNaBi)

Theoretical Values: C: 15.82, H: 1.98, O: 28.13, N: 3.08, Bi: 45.9, Na: 5.1

Measured value: C: 15.13, H: 1.88, O: 27.60, N: 3.01, Bi: 45.2, Na: 4.9

Example 6: Preparation of Ammonium Potassium Oxybismuthyl Citrate

47.3 g of the title compound was obtained by the same method as the Example 1, except that the following ingredients were used in the amounts described.

Bismuth Citrate 39.8g

Potassium Carbonate 6.9g

8.0 g ammonium bicarbonate (99%)

Elemental Analysis (C ₆ H ₉ O ₈ NKBi)

Theoretical Values: C: 15.28, H: 1.91, O: 27.17, N: 2.97, Bi: 44.4, K: 8.3

Measured value: C: 15.07, H: 1.81, O: 27.20, N: 2.85, Bi: 43.7, K: 8.1

Representative disodium oxybismuthyl citrate and dipotassium oxybismuthyl straight among the compounds of the present invention were tested as follows for the anti-ulcer effect and the antimicrobial effect against Helicobacter pyrroli.

Experimental Example 1

Ulcer Inhibitory Effect Experiment

Sprague-Dawley rats weighing 200 ± 20 g were divided into four groups of 15 rats per group. After fasting all mice for 10 hours, group 3 mice received a dose of 120 mg / kg disodium oxybismuthyl citrate, and group 4 mice received 120 mg / dipotassium dipotassium oxybismuthyl citrate. At the dose of kg, bismuth subcitrate was dosed at 120 mg / kg in group 2 (comparative group), and the same volume of physiological saline was orally administered to the remaining group 1 (control). Immediately after administration of the drug, an intraperitoneal injection of ulcer trigger indomethacin was administered at a dose of 3 mg / kg. All mice were left at 4 ° C. for 6 hours and then killed, and the length of the ulcers formed in the stomach was measured. The average value (± standard deviation) is shown in Table 1 below.

Experimental Example 2

Antimicrobial Effects on Helicobacter Pyrroli

A total of 10 strains were used in the experiment, including 9 strains of Helicobacter pyrroli isolated from patients with gastric diseases in Gyeongsang National University Medical School and 1 strain isolated from Warren and Marshall in 1983. Mueller-Hinton medium with 10% horse serum was used as the medium. Culture conditions were 8 to 10% CO and filled with sufficient humidity in a 37 ℃ incubator and cultured for 7 days or more to observe the colonies. Helicobacter pyrroli strains were determined by gram staining and urease testing of colonies formed. That is, the strain was inoculated on the medium and incubated at 37 ° C. for 24 hours, and then the strain was observed as red color by observing the cluster. Gram staining was used to control staining with Carbolfuchsin instead of Safranine O, and Christensen's urea broth was used for the urease test. Minimum Inhibitory Concentration (MIC) of the samples was determined by agar plate dilution. The results are shown in Table 2 below. Bismuth subcitrate and the antibiotic vancomycin were used as comparative drugs.

As can be seen in Tables 1 and 2, the bismuth compounds of the present invention showed an excellent ulcer inhibitory effect compared to bismuth subcitrate, and even better than vancomycin as well as bismuth subcitrate in the antimicrobial experiments for Helicobacter pyrroli. The effect was shown.

As described above, the new bismuth compounds of the present invention have excellent antiulcer and antihelicobacter pyrroli effects and relatively simple chemical structures, which are useful as co-administration with other drugs, as well as in the preparation of mixed compositions and in the future as reaction intermediates of new derivatives. It can be used easily and excellent in water solubility, it can be seen that the compound is particularly useful in the preparation and use of liquid form. In addition, the production method of the present invention not only can obtain a high-purity target compound in high yield by using a low-temperature reaction and a freeze-drying method, but also the production process is relatively simple, which is a very advantageous method for industrial practice. Able to know.

Claims (13)

The water-soluble bismuth compound of following general formula (I) whose bismuth content which is an active ingredient is 40 to 47 weight%. Wherein M ₁ and M ₂ are selected from Na, K and NH ₄ and may be the same or different, respectively. The compound of formula (I) according to claim 1, wherein the compound of formula (I) is disodium oxybismuthyl citrate, dipotassium oxybismuthyl citrate, diammonium oxybismuthyl citrate, potassium sodium oxybismuthyl citrate, A water-soluble bismuth compound selected from the group consisting of ammonium sodium oxybismuthyl citrate and ammonium potassium oxybismuthyl citrate. Bismuth citrate represented by the following structural formula (II) is dispersed in water having a volume of about 2 to 5 times, and then at least one compound selected from hydroxides of alkali metals, carbonates of alkali metals, and carbonates of ammonia is added to bismuth citrate. To quantitatively added in a water solvent in an equivalent ratio of 1: 2 to react for 2 to 10 hours to prepare a transparent solution, the solution is dried according to the method selected from high temperature concentration, spray or freeze drying method A method for producing a water-soluble bismuth compound of formula (I). Wherein M ₁ and M ₂ are as defined in claim 1. 4. The process according to claim 3, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide. 4. The process according to claim 3, wherein the alkali metal carbonate is selected from sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. The manufacturing method of Claim 3 whose carbonate of ammonia is ammonium carbonate or ammonium bicarbonate. The production method according to any one of claims 3 to 6, wherein the alkali compound is added alone or in combination of two or more thereof. The process according to claim 3, wherein the final pH of the reaction solution is in the neutral range of 6-8. The method of claim 8, wherein the final pH of the reaction solution is in the neutral range of 6.5 to 7.5. The manufacturing method of Claim 3 whose reaction temperature is 0-30 degreeC. The manufacturing method of Claim 10 whose reaction temperature is 0-10 degreeC. The production method according to claim 3, wherein the drying method is a freeze drying method. A pharmaceutical composition for treating ulcers comprising a water-soluble bismuth compound of the general formula (I) below as an active ingredient and a pharmaceutically acceptable carrier. Wherein M ₁ and M ₂ are as defined in claim 1.