KR19980035382A - Novel biphenyl dicarboxylic acid derivatives and preparation method thereof - Google Patents

Abstract

The present invention relates to a novel biphenyl dicarboxylic acid derivative represented by the following formula (1), which is effective for improving liver damage and treating hepatitis, and a method of preparing the same.

Formula 1

In the above formula, M ₁ and M ₂ are the same as or different from each other and are alkali metal atoms.

Description

Novel biphenyl dicarboxylic acid derivatives and preparation method thereof

The present invention relates to a novel biphenyl dicarboxylic acid derivative represented by the following formula (1), which is effective for improving liver damage and treating hepatitis, and a method of preparing the same.

[Formula 1]

In the above formula, M ₁ and M ₂ are the same as or different from each other and are alkali metal atoms.

In general, biphenyl dicarboxylic acid derivatives are well known to have a therapeutic effect on hepatitis, in particular, dimethyl 4,4'-dimethoxy-5,6,5 ', 6'-dimethyl represented by the following Chemical Formula 2 Rendioxy biphenyl dicarboxylate (hereinafter referred to as DDB) is currently commercialized as a therapeutic agent for hepatitis.

[Formula 2]

D.D.B., which is represented by Chemical Formula 2, is a synthetic derivative having a chemical structure similar to that of SchiSandrin C extracted from SchiSandrae component which shows an effect of improving liver function. DDB suppresses the destruction of liver cells by viruses, toxic substances, drugs, etc., and normalizes liver function, especially serum transaminases of hepatitis patients. Among them, serum glutamate pyruvate transamines (hereinafter referred to as S-GPT) levels Effective for normalizing The manufacturing method and physical properties of D.D.B. are described in detail in Japanese Patent Application Laid-open No. 60-209582.

However, DDB is known to be effective in normalizing S-GPT levels in terms of efficacy, but hardly effective in normalizing serum glutamate oxaloacetic acid transaminases (hereinafter referred to as S-GOT) (European patent). Published 90-353358). In addition, as shown in the formula (2), the chemical structure of the DDB is generally composed of a structure of a poorly soluble biphenyl group, methyl ester group, alkylphenyl ether group, etc., so that the solubility in water in the physical properties 0.01% (W / W It is very poorly soluble so that the absorption rate in the gastrointestinal tract is low, and the bioavailability is reported to be very low (30% or less) (Solubilization and design of soft capsule agent of biphenyldimethyldicarboxylate, Vol. 26, No. 26). It is.

In addition, due to the poor solubility of D.D.B., it is impossible to use it in the formulation of oral liquid or injection, and has a disadvantage of being limited to solid preparations such as oral tablets and capsules.

The present inventors have begun a study of a new biphenyl dicarboxylate derivative in order to improve the shortcomings of D.D.B. As a result, the level of S-GPT as well as the normalization of S-GOT at the same time has an excellent effect in the treatment of hepatitis, and also has a high solubility in water, a new biphenyl dicar can be formulated as an oral solution or injection The present invention has been completed by synthesizing a carboxylate derivative.

Accordingly, the present invention provides a novel water-soluble biphenyl dicarboxylate derivative, a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient, which is excellent in improving liver function and is water-soluble, which can be used as an oral solution or injection. There is a purpose.

1A is an I.R. spectrum of disodium 4,4'-dimethoxy-5,6,5 ', 6'-dimethylenedioxy biphenyl dicarboxylate,

1B is the H ¹ -NMR spectrum of disodium 4,4'-dimethoxy-5,6,5 ', 6'-dimethylenedioxy biphenyl dicarboxylate,

2A is an I.R. spectrum of dipotassium 4,4'-dimethoxy-5,6,5 ', 6'-dimethylenedioxy biphenyl dicarboxylate,

2b is the H ¹ -NMR spectrum of dipotassium 4,4'-dimethoxy-5,6,5 ', 6'-dimethylenedioxy biphenyl dicarboxylate,

3A is an I.R. spectrum of potassium sodium 4,4'-dimethoxy-5,6,5 ', 6'-dimethylenedioxy biphenyl dicarboxylate,

3B is the H ¹ -NMR spectrum of potassium sodium 4,4'-dimethoxy-5,6,5 ', 6'-dimethylenedioxy biphenyl dicarboxylate.

The present invention is characterized by a biphenyl dicarboxylic acid derivative represented by the following formula (1).

Formula 1

In the above formula, M ₁ and M ₂ are the same as or different from each other and are alkali metal atoms.

In addition, the present invention is to disperse the compound represented by the following formula (2) in a mixed solvent of water and lower alcohol, and then added to the alkali metal hydroxide aqueous solution to heat the reaction, and then adjust the pH of the reaction solution around 7 and then reduced pressure Another method is to prepare a biphenyl dicarboxylate derivative represented by Chemical Formula 1 by concentrating and dropwise adding acetone to precipitate a target compound.

Formula 2

In addition, the present invention is a biphenyl dicarboxylate derivative represented by the formula (1) as an active ingredient, wherein the pharmaceutical composition for improving liver damage or a pharmaceutical composition for treating hepatitis containing a pharmaceutically acceptable carrier It is another feature.

Referring to the present invention in more detail as follows.

The present invention relates to a novel biphenyl dicarboxylate derivative that can be formulated as an oral solution or an injection for the preparation of a medicament for improving liver function or treating hepatitis due to its excellent liver function and solubility in water.

In the biphenyl dicarboxylate derivative represented by Formula 1 according to the present invention, particularly preferred compounds are as follows.

Disodium 4,4'-dimethoxy-5,6,5 ', 6'-dimethylenedioxy biphenyl dicarboxylate,

Dipotassium 4,4'-dimethoxy-5,6,5 ', 6'-dimethylenedioxy biphenyl dicarboxylate,

Potassium sodium 4,4'-dimethoxy-5,6,5 ', 6'-dimethylenedioxy biphenyl dicarboxylate.

The preparation process of the biphenyl dicarboxylate derivative represented by Chemical Formula 1 according to the present invention is as follows.

First, D.D.B represented by Chemical Formula 2 is dispersed in a mixed solvent of water and a lower alcohol. It is preferable to use about 10 to 20 weight times of the mixed solvent. When the amount of the mixed solvent is less than 10 weight times, the amount of dissolution of the reaction starting material DDB is small, and thus the reaction progress is slowed and exceeds 20 weight times. Excessive use is not economically desirable. The mixing ratio of water and lower alcohol is maintained at a volume ratio of 8: 2 to 2: 8, preferably 4: 6 to 6: 4, and this range maintains a constant concentration of DDB and alkali metal hydroxide, which are reaction starting materials. It is to maintain.

Then, an aqueous alkali metal hydroxide solution is added to the dispersion and heated for about 4 to 10 hours. The alkali metal hydroxide used at this time may be used alone or in combination of two or more, particularly preferably using sodium hydroxide, potassium hydroxide or a mixture thereof. Alkali metal hydroxides are added in an equivalent ratio of 1: 2.1 to 1: 2.2 relative to D.D.B., and when the amount is less than 2.1 equivalents, the reaction is difficult to complete, and it is not economically desirable to add unnecessary alkali in excess of 2.2 equivalents. In addition, the temperature of the heating reaction is to maintain 60 ~ 100 ℃, preferably 70 ~ 90 ℃, if the reaction temperature is less than 60 ℃ slow reaction rate, if it exceeds 90 ℃ most of the boiling point of the reaction solvent Therefore, further heating is undesirable.

When the reaction proceeds sufficiently, the pH of the reaction solution is adjusted to 6-8, preferably 7, and then concentrated under reduced pressure to obtain a residue. Then, 4-6 weight times of acetone is added dropwise to the residue to precipitate the compound represented by Chemical Formula 1 as an object of the present invention. Preference is given to using 1N hydrochloric acid as a neutralizing agent for pH adjustment.

In order to increase the purity of the target compound represented by the formula (1) additionally using a lower alcohol to perform the recrystallization process, as a result it was possible to obtain a high purity compound of more than 99.0% in a high yield of more than 90%.

The lower alcohols used as reaction solvents or recrystallization solvents during the preparation process according to the present invention are alcohol compounds having 1 to 3 carbon atoms, and more specifically, methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol. . If higher alcohols having 4 or more carbon atoms are used instead of lower alcohols, the solubility of the target compound is significantly reduced, resulting in very low production yields.

The basic technical configuration of the production method of the present invention as described above is to remove the methyl group by the alkali hydrolysis reaction of D.D.B, and to bind an alkali metal ion useful for preparing a water-soluble salt thereto.

In general, administration as an injection compared to oral preparations is highly desirable for obtaining a rapid medicinal effect. From this point of view, DDB has a low solubility of 0.01% (W / W) or less in water, making it difficult to be used as a formulation for oral solutions or injections. However, the compound represented by Formula 1 according to the present invention is 1% ( Because of its high solubility over w / w), it can be used as a topical agent, which can be very useful for patients with acute liver failure. In addition, the compound represented by the formula (1) according to the present invention shows a neutral range of pH 6 _to 8 in a 10% aqueous solution, so that when orally administered it is quickly dissolved in the gastrointestinal tract to be present in a drug molecule that is easy to absorb The bioavailability is markedly improved, thereby significantly reducing the amount of drug used.

Accordingly, the present invention may be formulated into a general oral preparation and an injection formulation by containing at least one or more biphenyl dicarboxylate derivatives represented by Formula 1 as an active ingredient.

Examples of oral preparations include tablets, capsules, pills, and intraocular solutions. Solid preparations such as tablets, capsules, pills, and the like are prepared by containing pharmaceutically acceptable carriers commonly used in addition to active ingredients, that is, suitable excipients, binders, lubricants, coloring agents, coating agents, sweeteners, and the like. It is prepared by containing a suitable sweetener, fragrance, colorant, preservative, etc., including water. In order to formulate an injection, suitable solvents, excipients, preservatives and the like commonly used are used, and both solution injection and powder injection are applicable.

Hereinafter, the present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1 Preparation of Disodium 4,4'-Dimethoxy-5,6,5 ', 6'-Dimethylenedioxy Biphenyl Dicarboxylate

Dimethyl 4,4'-dimethoxy-5,6,5 ', 6'-dimethylenedioxy biphenyl dicarboxylate (20 g) in a mixed solvent of purified water (100 mL) and methyl alcohol (150 mL) Then, a solution of sodium hydroxide (purity 99%, 4.2 g) dissolved in purified water (50 mL) was slowly added dropwise at room temperature for 1 hour. After the dropwise addition, a cooler was attached and the reaction temperature was raised to 75-80 ° C. and stirred for 6 hours.

After completion of the reaction, 1N hydrochloric acid was added dropwise to adjust the pH to around 7.0, the reaction solution was concentrated under reduced pressure, and acetone (100 mL) was slowly added dropwise to the residue for 1 hour. After the addition, the mixture was stirred at room temperature for 2 hours, and the white powder obtained by filtration under reduced pressure was recrystallized with methyl alcohol (1 L) to obtain 19.8 g (yield 95.4%, purity 99.5%) of the title compound. IR and H ¹ -NMR spectra of this compound are shown in FIGS. 1A and 1B, respectively.

Elemental Analysis (C ₁₈ H ₁₂ O ₁₀ Na ₂ ) Results

Theoretical value: C: 49.77, H: 2.76, O: 36.87, Na: 10.60

Measured value: C: 48.89, H: 2.84, O: 37.12, Na: 10.43

Example 2 Preparation of Dipotassium 4,4'-Dimethoxy-5,6,5 ', 6'-Dimethylenedioxy Biphenyl Dicarboxylate

Prepared in the same manner as in Example 1 except that sodium hydroxide (purity 99%, 4.2 g) was used instead of potassium hydroxide (purity 95%, 6.0 g). As a result, 21.4 g (yield 96.0%, purity 99.8%) of the title compound as a white powder was obtained. IR and H ¹ -NMR spectra of this compound are shown in FIGS. 2A and 2B, respectively.

Elemental Analysis (C ₁₈ H ₁₂ O ₁₀ K ₂ )

Theoretical value: C: 46.33, H: 2.57, O: 34.32, Na: 16.77

Measured value: C: 46.58, H: 2.46, O: 33.79, Na: 16.44

Example 3: Preparation of Potassium Sodium 4,4'-Dimethoxy-5,6,5 ', 6'-Dimethylenedioxy Biphenyl Dicarboxylate

Prepared in the same manner as in Example 1 except using sodium hydroxide (purity 99%, 2.1 g) and potassium hydroxide (purity 95%, 3.0 g) instead of sodium hydroxide (purity 99%, 4.2 g). As a result, the title compound (20.6 g, yield 95.7%, purity 99.3%) was obtained as a white powder. IR and H ¹ -NMR spectra of this compound are shown in FIGS. 3A and 3B, respectively.

Elemental Analysis (C ₁₈ H ₁₂ O ₁₀ Na K) Results

Theoretical value: C: 47.99, H: 2.67, O: 35.55, Na: 5.11, K: 8.69

Measured value: C: 48.63, H: 2.52, O: 35.40, Na: 5.23, K: 8.37

Experimental Example 1: Solubility Measurement

After dissolving each compound in 10 ml of distilled water at room temperature, the insolubles were filtered, the aqueous solution was concentrated to dryness, and the solubility of each compound was measured by measuring the residual amount. The results are shown in Table 1 below.

Compound people Solubility (g / water 100ml) Disodium 4,4'-dimethoxy-5,6,5 ', 6'-dimethylenedioxy biphenyl dicarboxylate (Example 1) Dipotassium 4,4'-dimethoxy-5,6,5 ', 6'-dimethylenedioxy biphenyl dicarboxylate (Example 2) potassium sodium 4,4'-dimethoxy-5,6,5', 6'-dimethylenedioxy biphenyl dicarboxylate Example 3 DBB 110 or more 130 or more 120 or more 0.01

The solubility in water of each of the compounds prepared according to Examples 1 to 3 according to the invention is at least 10,000 times compared to D.D.B.

Experimental Example 2: Soy liver improvement effect experiment

Healthy Sprague of body weight 230 _~ 250g - an improvement to the liver the effects of the compound prepared above is carried out using male rats system we (Sprague-Dawley) to experimental animals in Example 1 and Example 2 were tested.

The experimental animals were divided into four groups of 10 animals per group. Group 1 was treated with 1 ml of purified water, and group 2 was orally administered with DDB twice a day for 5 days, twice a day for 120 mg / kg as a control group, and group 3 was prepared with the compound prepared in Example 1, respectively. 120 mg / kg twice a day orally administered 10 times a total of 5 days, and in the fourth group, the compounds prepared in Example 2 were each orally administered 10 times twice a day for 5 days at 120 mg / kg each.

Four days after the first drug administration, 1.2 ml / kg of carbon tetrachloride was diluted in the same amount of olive oil and injected intraperitoneally to induce liver damage. Rats were anesthetized with ether and blood was collected from the abdominal aorta 24 hours after the administration of carbon tetrachloride. It was.

Serum was obtained by centrifugation after leaving the blood for 1 hour and used for measuring enzyme activity such as GOT, GPT, Akaline Phosphatase (ALP). The experimental results are shown in Table 2 below.

GPT (U / L) GOT (U / L) ALP (U / L) Control D.D.B. Compound of Example 1 Compound of Example 2 1361 ± 96691 ± 165 ^** 690 ± 104 ^** 718 ± 150 ^** 1798 ± 1351821 ± 386 1000 ± 215 ^** 1143 ± 278 384 ± 51285 ± 37 ^* 239 ± 25 ^* 227 ± 18 ^{* *} P 0.05, ^** P 0.01

As shown in Table 2, the compounds according to the present invention lowered the GPT value to the same degree as the conventional D.D.B. compared to the control group, and the ALP value was lower than the conventional D.D.B. Lower than In particular, while D.D.B. has almost no difference in lowering the GOT value, the compounds according to the present invention showed an excellent effect of significantly lowering the GOT value compared to the control.

As described above, the biphenyl dicarboxylate derivatives represented by Chemical Formula 1 of the present invention are excellent in improving liver damage and water solubility is not comparable with conventional drugs, and thus have high bioavailability and various forms. Since formulation is possible, it can be seen that the compound is very advanced compared to the conventional drug.

In addition, the production method of the present invention can be obtained in a high yield of the target compound of high purity and the manufacturing process is also relatively simple, it can be seen that it is a very useful method for industrial practice.

Therefore, the compound of the present invention has an excellent effect of simultaneously normalizing the levels of S-GPT and S-GOT, and is very useful as an oral solution or injection for the purpose of improving liver function due to its high solubility in water.

Claims (15)

Biphenyl dicarboxylic acid derivative represented by the following formula (1). Formula 1 In the above formula, M ₁ and M ₂ are the same as or different from each other and are alkali metal atoms. According to claim 1, wherein the compound represented by Formula 1 Disodium 4,4'-dimethoxy-5,6,5 ', 6'-dimethylenedioxy biphenyl dicarboxylate, Dipotassium 4,4'-dimethoxy-5,6,5 ', 6'-dimethylenedioxy biphenyl dicarboxylate, and Biphenyl dicarboxylic acid derivative, characterized in that selected from potassium sodium 4,4'-dimethoxy-5,6,5 ', 6'-dimethylenedioxy biphenyl dicarboxylate. After dispersing the compound represented by the following formula (2) in a mixed solvent of water and lower alcohol, and then adding an alkali metal hydroxide aqueous solution to heat the reaction, the pH of the reaction solution was adjusted to around 7 and then concentrated under reduced pressure and acetone was added dropwise Method for producing a biphenyl dicarboxylate derivative represented by the following formula (1) characterized in that to precipitate by. Formula 2 Formula 1 In the above formula, M ₁ and M ₂ are the same as or different from each other and are alkali metal atoms. The method of claim 3, wherein the alkali metal hydroxide is selected from sodium hydroxide and potassium hydroxide. The method for producing a biphenyl dicarboxylate derivative according to claim 3 or 4, wherein the alkali metal hydroxide is used alone or in combination of two or more thereof. The method for preparing a biphenyl dicarboxylate derivative according to claim 5, wherein the alkali metal hydroxide is used in an amount of 2.1 to 2.2 equivalents relative to the compound represented by Chemical Formula 2. The method of claim 3, wherein the mixed solvent of water and lower alcohol is mixed at a volume ratio of 8: 2 to 2: 8. 8. The method of claim 7, wherein the mixed solvent of water and lower alcohol is mixed at a volume ratio of 4: 6 to 6: 4. The method for producing a biphenyl dicarboxylate derivative according to claim 3, wherein the heating reaction has a temperature of 70 to 90 ° C. The method of claim 3, wherein the precipitate is recrystallized using a lower alcohol. The method of claim 3 or 10, wherein the lower alcohol is selected from methyl alcohol, ethyl alcohol, n-propyl alcohol and isopropyl alcohol. A pharmaceutical composition comprising a biphenyl dicarboxylate derivative represented by the following Formula 1 as an active ingredient and a pharmaceutically acceptable carrier contained therein. Formula 1 In the above formula, M ₁ and M ₂ are the same as or different from each other and are alkali metal atoms. The method of claim 12, wherein the pharmaceutical composition is a liver disease treatment agent effective for improving liver damage and hepatitis. The method of claim 12, wherein the pharmaceutical composition is an injection. The method of claim 12, wherein the pharmaceutical composition is an oral solution.