WO1998021194A1

WO1998021194A1 - Novel biphenyl dicarboxylic acid derivatives and process for preparing them

Info

Publication number: WO1998021194A1
Application number: PCT/KR1997/000222
Authority: WO
Inventors: Jae Chul Kim; Hwan Bong Yoo; Choung Uk Park
Original assignee: Jae Chul Kim; Hwan Bong Yoo; Choung Uk Park
Priority date: 1996-11-13
Filing date: 1997-11-13
Publication date: 1998-05-22
Also published as: CN1235599A; JP2000503683A; AU5068798A; KR100344099B1; KR19980035382A; ID21896A

Abstract

The present invention relates to a novel biphenyl dicarboxylic acid derivative represented by formula (1), being effective for the treatment of liver disorder as well as hepatitis, and process for preparing them, wherein, M1 and M2 are the same or different, and each represents independently alkali metal atom.

Description

Novel biphenyl dicarboxylic acid derivatives and process for preparing them

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to a novel biphenyl dicarboxylic acid derivative represented by the following formula

(1), being effective for the treatment of liver disorder as well as hepatitis, and process for preparing them.

,0

Wherein, Mi and M₂ are the same or different, and each represents alkali metal atom.

Description of the Prior Art

15 In general, biphenyl dicarboxylic acid derivatives have been reported to be effective for the treatment of hepatitis and in particular, dimethyl 4,4'-dimethoxy-5,6,5' ,6 '-dimethylenedioxy biphenyl dicarboxylate(hereinafter referred to as "D.D.B"), represented by the following formula (2), has been commercialized

20 as an antihepatitis agent.

The D.D.B represented by the above formula (2), which is effective for the treatment of liver disorder, is a synthetic derivative having the similar chemical structure to Schisandrin C extracted from Schisandrae Fructus. The D.D.B serves to inhibit the destruction of liver cells associated with virus, toxins, or drugs. The D.D.B is also effective for the enhancement of the hepatic function, in particular, for serum transaminase values in patients with hepatitis, i.e., serum glutamic-pyruvic transaminase (hereinafter referred to as "S-GPT") values. The process of preparing the D.D.B and its physical properties were described in the Japanese Patent Unexamined Publication Sho 60-209582 in more detai 1. Even though the D.D.B. is highly effective in normalizing the S-GPT values in terms of efficacy, it is little effective in normalizing the serum glutamic-oxaloacetic transaminase(hereinafter referred to as "S-GOT") values [Europe Patent Unexamined Publication No. 90-353358]. As noted in the above formula (2), since its chemical structure is generally composed of water-insoluble biphenyl group, methylester group and alkylphenyl ether group, the D.D.B. represents extremely low solubility to water of less than 0.01% (w/w). In this context, it was reported that its poor absorptivity in the gastro-intestinal tract was responsible for less than 30% bioavai labi lity in the human body[The Pharmaceutical Society of Korea, Vol. 26, No. 1 "solubilization of biphenyldimethyl dicarboxylate and its design into soft capsule"].

Furthermore, due to the fact that the D.D.B is insoluble in water, its formulation intended for oral solution or injectable dosage form is unavailable, thus restricting to solid forms such as oral tablet or capsule.

To overcome the shortcomings associated with the D.D.B represented by the above formula (2), the inventor et al . have carried out long-term studies for the research of a novel biphenyl dicarboxylate derivative and completed the present invention by synthesizing a novel biphenyl dicarboxylate derivative having excellent therapeutic effect on hepatitis by simultaneously normalizing both S-GPT and S-GOT values. Now that the above compound has a high solubility to water, it may be formulated as an oral solution or injection.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a novel water-soluble biphenyl dicarboxylate derivative having an excellent therapeutic effect on the liver and enabling to formulate some dosage forms such as oral solution or injection, its preparing method and a pharmaceutical composition containing it as an active ingredient . Brief Description of the Drawings

Fig. la is an I.R. spectrum of disodium 4,4'-dimethoxy- 5,6,5' ,6' -dimethylenedioxy biphenyl dicarboxylate;

Fig. lb is a H -NMR spectrum of disodium 4,4'-dimethoxy- 5,6,5' ,6'-dimethylenedioxy biphenyl dicarboxylate!

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

Fig. 2b is a H^X-NMR spectrum of dipotassium 4,4'-dimethoxy- 5,6,5' ,6'-dimethylenedioxy biphenyl dicarboxylate!,

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

Fig. 3b is a H -NMR spectrum of potassium sodium 4,4'- dimethoxy-5,6,5' ,6'-dimethylenedioxy biphenyl dicarboxylate.

Detailed Description of the Invention

The present invention relates to biphenyl dicarboxylic acid derivative represented by the following formula (1):

Wherein, Mi and M₂ are the same or different, and each represents alkali metal atom. Further, the present invention relates to a process of preparing biphenyl dicarboxylate derivative represented by the above formula (1), wherein it comprises:

Dispersing the compound represented by the formula (2) into a co-solvent containing water and lower alcohol;

Adding alkali metal hydroxide solution to the said mixture for heating reaction!

Adjusting the pH of the reacting solution at about 7 and concentrated under reduced pressure!

Adding acetone dropwise to the said reacting solution to deposit a desired compound.

Also, the present invention relates to a drug composition containing biphenyl dicarboxylate derivative, represented by the above formula (1), as an active ingredient together with a pharmaceutically acceptable carrier, for the treatment of hepatic disorder as well as hepatitis,

The present invention is explained in more detail as set forth hereunder . The present invention relates to a novel biphenyl dicarboxylate derivative having excellent hepatic effect and better solubility to water. Thus, this derivative may be formulated in the dosage form of oral solution or injection designed for the treatment of hepatic disorder as well as hepatitis.

In particular, the desirable biphenyl dicarboxylate derivatives according to the present invention, represented by the above formula (1), include 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 biphenyl dicarboxylate derivative according to the present invention, represented by the the above formula (1), is prepared by the following processes:

First, the D.D.B, represented by the above formula (2), is dispersed into a co-solvent containing water and lower alcohol. It is preferred to use the co-solvent in the range of about 10 ~ 20 weight times to the D.D.B; if the co-solvent content is less than 10 weight times, less solubilizing D.D.B amount as a starting material causes a slower reaction rate and in case of exceeding 20 weight times, it is not economical. The mixing ratio between water and lower alcohol is in the range of 8:2 ~ 2:8 as a volume ratio and it is preferred to maintain the volume ratio of 4:6 ~ 6:4. Such ratio is intended for keeping the concentration of both the D.D.B, a starting material, and alkali metal hydroxide in a constant level .

Then, a solution of alkali metal hydroxide is added to the said dispersing solution and reacted under heating about 4 — 10 hours. Hence, alkali metal hydroxide for this reaction is mono compound or mixture thereof and it is in particular preferred to use sodium hydroxide, potassium hydroxide or its mixture. The content of alkali metal hydroxide is added to the D.D.B in the equivalent ratio of 1:2.1 ~ 1:2.2; if the content is in the equivalent ratio of less than 2.1, it is difficult to complete the reaction and in case of adding unnecessary alkali by exceeding the equivalent ratio of 2.2, it is not economical. Also, the temperature of the said heating reaction is in the range of 60 ~ 100^°C and it is preferred to maintain the temperature at 70 ~ 90^°C . If the reaction temperature is less than 60^°C , the reaction rate becomes slow and in case of exceeding 100^°C , the reaction temperature will exceed a boiling point of co-solvent. Therefore, any heating beyond the above temperature is not desirable.

When the said reaction is sufficiently carried out, the pH of the reacting solution is adjusted at 6 ~ 8, preferably at 7 and then, concentrated under reduced pressure to obtain a residue. Acetone is added to the residue in the range of 4-6 weight times so as to deposit a compound represented by the above formula (1).

It is preferred to use IN HC1 as a neutralizer for adjusting the pH.

In order to enhance the purity of a desired compound represented by the above formula (1), a recrystallization process is additionally carried out using a lower alcohol and as a result, a high-purity compound of more than 99.0% may be obtained with higher yield of more than 90%.

Some lower alcohol used as a reaction or recrystallization solvent in the preparing process according to the present invention is an alcohol compound having 1 — 3 carbons and, more specifically, it includes methyl alcohol, ethyl alcohol, n-propyl alcohol and isopropyl alcohol. If some higher alcohol having more than 4 carbons is used instead of a lower alcohol, the solubility of a desired compound is significantly reduced so that its yield becomes extremely low.

According to the preparing method according to the present invention as aforementioned, the basic technical structure is that some methyl group is removed from methylester bonding of the D.D.B via alkali hydrolysis and then, combined with alkali metal ion useful for the preparation of water-soluble salt.

In general, the most preferable administration method for an immediate onset of efficacy is based on injectable compared to oral preparations. In this respect, since the D.D.B has a low solubility to water, less than 0.01%(w/w), its actual formulation towards oral solution or injection has been unavailable. In comparison, a compound of the present invention, represented by the above formula (1), has higher solubility of more than 100%(w/w) and its available dosage form such as injection may be very effectively administered to patients with acute hepatic disorder. Further, since a compound, represented by the said formula (1), shows the neutral pH of 6 — 8 in 10% aqueous solution, it is promptly absorbed from the gastro-intestinal tract via oral administration, thus being present as absorption-available drug molecules. Thus, its significantly enhanced bioavai labi lity will contribute to further reduction in the dosage of drug. Therefore, the present invention contains at least one biphenyl dicarboxylate derivative or more as active ingredient, represented by the above formula (1), thus making it possible to formulate some dosage forms such as oral and injectable preparations.

The oral preparations include tablets, capsules, pills and oral solution. In addition to active ingredients, the solid preparations such as tablets, capsules and pills may be prepared by containing appropriate amounts of some commonly available and pharmaceutically acceptable carriers such as excipients, binders, lubricants, colorants, coating agents and sweeteners. The oral solution may be also prepared by containing appropriate amounts of sweeteners, flavoring agents, colorants and preservatives including water as a diluent. The injections of both solution and powder may be formulated by containing commonly available solvents, excipients and preservatives.

The present invention is explained in more detail by the following examples but is not limited by these examples.

Example l: 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) was added to a co-solvent containing purified water (100 IIU?,) and methyl alcohol (150 ml) and then, a solution of sodium hydroxide(purity: 99%, 4.2 g) dissolved in purified water(50 nE) was slowly added dropwise to the said mixture at room temperature for 1 hour. After the addition was completed, a condenser was attached to the reactor and the reaction temperature was raised to 75 ~ 80^°C , then the solution was stirred for 6 hours. When the reaction was completed, IN HC1 was added dropwise to the solution for adjusting the pH at about 7.0 and was concentrated under reduced pressure to obtain the residue. Acetone(100 mi ) was slowly added dropwise to the said residue for 1 hour. Then, the mixture was stirred at room temperature for 2 hours and sucction filtered to give a white powder. The powder was recrystallized with methyl alcohoKl SI ) to obtain a title compound 19.8g(yield: 95.4%, purity: 99.5%). The IR and H^NMR spectrum of this compound were represented in Fig. la and lb, respectively.

Theoretical values: C(49.77), H(2.76), 0(36.87), Na(10.60) Measured values: CC48.89), H(2.84), 0 (37.12), Na(10.43)

Example 2: Preparation of dipotassium 4,4'-dimethoxy-5,6,5' ,6'- dimethylenedioxy biphenyl dicarboxylate

The same procedure as described in the said example 1 was carried out, except that potassium hydroxide(purity: 95%, 6.0 g) was used instead of sodium hydroxide(purity: 99%, 4.2 g). As a result, 21.4 g of a title compound (yield: 96.0%, purity: 99.8%) was obtained in white powder form. The IR and H^NMR spectrum of this compound were represented in Fig. 2a and 2b, respectively.

Theoretical values^'. C(46.33), H(2.57), 0(34.32), Na(16.77) Measured values: C(46.58, H(2.46), 0(33.79), Na(16.44) Example 3: Preparation of potassium sodium 4,4'-dimethoxy- 5,6,5' ,6'-dimethylenedioxy biphenyl dicarboxylate

The same procedure as described in the said example 1 was carried out, except that sodium hydroxide(purity: 99%, 2.1 g) and potassium hydroxide(purity: 95%, 3.0 g) was used instead of sodium hydroxide(purity: 99%, 4.2 g) . As a result, 20.6 g, of a title compound (yield: 95.7%, purity: 99.3%) was obtained in white powder form. The IR and H -NMR spectrum of this compound were represented in Fig. 3a and 3b, respectively.

Theoretical values: C(47.99), H(2.67), 0(35.55), Na(5.11), K(8.69) Measured values: C(48.63), H(2.52), 0(35.40), Na(5.23), K(8.37)

Experimental example 1 ^' Measurement of solubility Each compound was dissolved in 10ιn£ of distilled water at room temperature for saturation. Then, after filtering off some insoluble materials, aqueous solution was concentrated and dried. The solubility of each compound was measured by measuring the remaining amounts. Its results were shown in the following table 1.

Tabl e 1.

The solubility to water of each compound prepared in the examples 1 — 3 of according to the present invention was more than 10,000 times as high as that of the D.D.B.

Experimental example 2: Experiment for liver disorder improvement effects

Healthy male Sprague-Dawley rats, weighing 230 — 250g, were used for this experiment so as to assess the liver disorder improvement effects of some compounds prepared in the said examples 1 and 2.

Experimental animals were divided into 4 groups (each group: 10 animals). For the first group served as control, 1 mi of purified water was given. For the second group served as comparative group, the D.D.B at a dose of 120 mg/kg was orally given two times daily for a period of 5 days (totalling 10 times). For the third group, a compound prepared in the example 1 at a dose of 120mg/kg was orally given two times daily for a period of 5 days (totalling 10 times). For the fourth group, a compound prepared in the example 2 at a dose of 120mg/kg was orally given two times daily for a period of 5 days (totalling 10 times).

4 days after drug initial administration, carbon tetrachloride (1.2 ml/kg) diluted in an equal volume of olive oil was intraperitoneally administered to rats so as to induce the liver impairment. 24 hours after administration of carbon tetrachloride, rats were anesthetised with ether and blood samples were collected from the abdominal aorta.

The blood was left for 1 hour and centrifuged. The serum, so obtained, was used for the measurement of enzymatic activities such as S-GOT, S-GPT and akaline phosphatase(ALP). The results of the experiment was shown in the following table 2.

Table 2.

From the said table 2, it is noted that compared to control, two compounds of according to the present invention lowered the S- GPT value at the same level as the conventional D.D.B, while further lowering the ALP value more than the conventional D.D.B. Whereas any significant difference was not observed between the D.D.B group and control in lowering the S-GOT value, two compounds of according to the present invention showed more remarkable therapeutic effects to significantly lower the S-GOT value than control .

As described in the above, biphenyl dicarboxylate derivatives, represented by the above formula (1) of the present invention, have the following advantages in that a) they are excellent in the treatment of liver disorder, b) since their water-soluble property is far superior to the conventional drugs, the bioavai labi lity is high and c) various dosage forms are available. Thus, the compounds of the present invention are more improved ones than the conventional drugs.

Also, the preparing method of the present invention is highly useful as an industrial method, since the desired compound with a high-purity may be obtained with high yield and the process is relatively simple. Therefore, the compound of the present invention are highly effective for normalizing the S-GPT and S-GOT values simultaneously. In addition, since the compound of the present invention has a high solubility to water, it is also efffective as oral solution or injection intended for the improvement of hepatic function.

Claims

CLAIMSWhat is claimed is:

1. A Biphenyl dicarboxylic acid derivative represented by the following formula (1):

The biphenyl dicarboxylic acid derivative according to claim 1, wherein the compound, represented by said formula (1), is selected from disodium 4,4 '-dimethoxy-5,6, 5' ,6 '-dimethylene^¬ dioxy biphenyl dicarboxylate, dipotassium 4,4'-dimethoxy- 5,6,5' ,6'-dimethylenedioxy biphenyl dicarboxylate, and potassium sodium 4,

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

A process of preparing biphenyl dicarboxylate derivative represented by the following formula (1), wherein it comprises:

Dispersing the compound represented by the formula (2) into a co-solvent containing water and lower alcohol; Adding alkali metal hydroxide solution to the said mixture for heating reaction; Adjusting the pH of the solution at about 7 and concentrated under reduced pressure! Adding acetone dropwise to the said solution for deposition thereof.

The process of preparing biphenyl dicarboxylate derivative according to claim 3, wherein said alkali metal hydroxide is selected from sodium hydroxide and potassium hydroxide.

5. The process of preparing biphenyl dicarboxylate derivative according to claim 3 or 4, wherein said alkali metal hydroxide is mono compound or mixture thereof.

6. The process of preparing biphenyl dicarboxylate derivative according to claim 5, wherein said alkali metal hydroxide is used in the equivalent ratio of 2.1 — 2.2 to the compound represented by said formula (2).

7. The process of preparing biphenyl dicarboxylate derivative according to claim 3, wherein a co-solvent containing said water and lower alcohol is mixed in the volume ratio of 8:2 - 2:8.

8. The process of preparing biphenyl dicarboxylate derivative according to claim 7, a co-solvent containing said water and lower alcohol is mixed in the volume ratio of 4:6 — 6:4

9. The process of preparing biphenyl dicarboxylate derivative according to claim 3, wherein said heating reaction is carried out in the range of 70 — 90^°C .

10 The process of preparing biphenyl dicarboxylate derivative according to claim 3, wherein said deposit is recrystallized a lower alcohol

11. The process of preparing biphenyl dicarboxylate derivative according to claim 3 or 10, where said lower alcohol is selected from methyl alcohol, ethyl alcohol, n-propyl alcohol and isopropyl alcohol.

12. A pharmaceutical composition containing biphenyl dicarboxylate derivative represented by the following formula (1) as an active ingredient, together with its pharmaceutically acceptable carriers.

Wherein, Mi and M2 are the same or different, and each represents alkali metal atom.

13. The pharmaceutical composition according to claim 12, wherein said composition is an effective hepatic agent which is a highly effective for the treatment of hepatic disorder as wel 1 as hepatitis.

14. The pharmaceutical composition according to claim 12, wherein said composition is an injection.

15. The pharmaceutical composition according to claim 12, wherein said composition is an oral solution.