JPH0635384B2 - Medicine containing quinone derivative as active ingredient - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a medicament containing a quinone derivative as an active ingredient. More specifically, the general formula [Where A is the formula Or a group represented by (Wherein X and Y mean the same or different hydroxyl groups or methoxy groups). n is 1
To an integer of 5] and a pharmacologically acceptable salt thereof as an active ingredient.

Ubidecarenone (aka CoenzymeQ ₁₀ , Ubiquinone ₁₀ )
Is a substance that was crystallinely isolated from bovine myocardial mitochondria by Crane et al. In 1957. It is widely distributed in the living body, especially in the intracellular mitochondria.
It is an important component of the electron transport system of mitochondria, which is an energy production system.

The present invention has conducted intensive studies for many years on these derivatives of ubidecarenone. However, in the structure of ubidecarenone, it was found that a compound group having a carboxyl group at the terminal of the polyprenyl chain has excellent physiological activity, and the present invention completed.

That is, the compound of the present invention has the general formula (I) [Where A is the formula Or a group represented by (Wherein X and Y mean the same or different hydroxyl groups or methoxy groups). n is 1
A quinone compound having a carboxyl group at the end of the polyprenyl chain represented by

The compound of the present invention has remarkably excellent phospholipase inhibitory action and antiplatelet action, and is useful as a thrombosis therapeutic agent based on these actions, for example, an antiplatelet agent and an antithrombotic agent. Specifically, cerebrovascular disorders such as TIA (transient cerebral ischemic attack), cerebral infarction (thrombus, embolism), cerebral arteriosclerosis,
Various embolisms including pulmonary embolism, postoperative thrombosis and embolism and blood flow disorder associated with vascular surgery and extracorporeal blood circulation,
Peripheral blood flow disorder due to occlusion or stenosis of limb arteries such as Buerger disease, live arteriosclerosis obliterans, collagen disease such as SLE, or white fistula, pancreatitis and DIC (disseminated intravascular coagulation syndrome), fundus vascular lesion due to diabetes Treatment and prevention of vascular disorders such as, and prevention of recurrence of these diseases and improvement of prognosis.

Furthermore, the chemical substance of the present invention is also effective for treating and preventing inflammatory diseases such as various rheumatic diseases.

The compound of the present invention can be produced by various methods, and one of the typical methods is as follows.

Manufacturing Method 1 In Formula (I), A is a formula (Wherein X and Y mean the same or different hydroxyl groups or methoxy groups), (In the formula, n means an integer of 1 to 5 and R means a hydrogen atom or a lower alkyl group.) That is, the compound (II) and the compound (III) are subjected to a condensation reaction using a catalyst such as silica alumina or silica gel-zinc chloride to obtain (I ') which is one of the target substances. In the formula (III), when R is a lower alkyl group, it is hydrolyzed with caustic potash, caustic soda or the like to give a carboxylic acid, which is referred to as (I ').

Production Method 2 In the formula (I), A is a formula In the case of the group shown by (In the formula, X, Y, and n have the above-mentioned meanings.) That is, the compound (I ') is treated with an oxidizing agent such as ferric oxide, lead oxide, etc. It may be a benzoquinone body represented by the formula (I ″).

Also, it can be obtained by a method such as the manufacturing method 1 or the manufacturing method 2.
The compounds according to the present invention include inorganic acids such as hydrochloric acid and sulfuric acid,
Salts can be formed with organic acids such as acetic acid, fumaric acid, or alkali metals such as sodium, potassium.
These salts can be obtained by subjecting the compound (I ′) or compound (I ″) obtained in the above Production Method 1 or Production Method 2 to a salt formation reaction by a usual method.

Next, experimental examples are given in order to describe the effect of the compound of the present invention in detail.

Experimental Example 1 Phospholipase A ₂ Inhibitory Action (1) Experimental Method Before quantifying the above-mentioned oxygen activity by quantifying myristinic acid released by phospholipase A ₂ using dimyristyl lecithin as a substrate, The test compounds shown below were added to the concentrations shown in Table 1 below, and their effects were examined.

CoQ ₁₀ was used as a comparative example.

Compound A: Compound B: Compound C: Compound D: The results are shown in Table 1. The values in Table 1 are for saline.
The numerical value of the test compound when 0 is shown, showing the phospholipase A ₂ inhibitory action.

From Table 1 above, it is clear that the compound of the present invention has a remarkable phospholipase A ₂ inhibitory action as compared with CoQ ₁₀ .

Example 2 Antiplatelet action on human platelets The compound of the present invention has an inhibitory action on human platelet aggregation in v
I considered itro. Platelet aggregation is caused by PAF (platelet act
ivating factor ...... 1-alkyl-2-acetyl-sn-
Glycero-3-phosphocholine), collagen, and A
An experiment was conducted by the following method using DP as an inducer.

(1) Platelet rich plasma
The blood was collected from the brachial vein of a healthy adult male at a ratio of 9 volumes of blood to 1 volume of 3.8% sodium citrate solution. Blood is 10
The PRP separated into the supernatant was collected by centrifugation at 0 × g for 8 minutes.

(2) Measurement of platelet aggregation To 0.2 ml of PRP prepared by the above method, add 25 μl of sample solution of various concentrations, incubate at 37 ° C for 3 minutes, and add 25 μl of the above inducer solution to induce aggregation. did. As an inducer, PAF 100 ng / ml, collagen 1 μg / ml, and ADP 5 μM were added at final concentrations.
Platelet aggregation is aggregomet manufactured by Nikko Bioscience
method of Mustard et al. [Mustard, JF, Hegaldt, B., R
owsell HC, MacMillan, RCJLab.clin.Med. 64 , 548-55
9 (1964)]. The inhibitory effect of the test compound was judged by the inhibitory rate against the aggregating ability of vehicle-added PRP as a control.

(3) Test compounds are as follows.

The compounds A to D are as shown in Experimental Example 1.

Compound E: Compound F: Compound G: Compound H: Compound I: Compound J: (4) The results are shown in Table 2.

The numerical values in Table 2 show the inhibition rate (%).

From Table 2, it is clear that the compound of the present invention has an excellent antiplatelet effect as compared with CoQ ₁₀ .

Next, the toxicity of the compound of the present invention will be described.

Toxicity Experiment For compounds A to J of the present invention, ddY mouse ♂ (body weight about 25 to 3
When the acute toxicity test was conducted using 0 g), the LD ₅₀ was 500 mg / kg or more in all cases by oral administration. Also,
When the compounds A to J of the present invention were injected through the tail vein of the above-mentioned mice (10 mice), the survival rate was 100% at 10 and 10 mg / kg, 30 mg / kg and 100 mg / kg, respectively. Therefore, the LD ₅₀ is 100 mg / kg or more).

A drug based on the phospholipase inhibitory action of the compound of the present invention,
When used as a drug based on antiplatelet action, specifically, as a therapeutic / preventive agent for inflammatory diseases such as various antiplatelet agents, antithrombotic agents, therapeutic agents for heart diseases, and rheumatic diseases,
Oral or parenteral administration (intramuscular, subcutaneous, intravenous,
Suppositories). The dose varies depending on the difference in disease, symptoms, age of the patient, etc., but is usually about 10 mg to 1,000 mg, preferably about 50 mg to 500 mg per day for an adult.

In order to formulate the compound of the present invention, a dosage form such as a tablet, a granule, a powder, a capsule, an injection, a suppository, etc. is prepared by a method commonly used in the technical field of preparation.

That is, when preparing a solid preparation for oral use, an excipient, and if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc. are added to the main drug, and then tablets or Inflatable tablets, granules, powders, capsules, etc.

Examples of excipients include lactose, corn starch, sucrose,
Glucose, sorbit, crystalline cellulose, etc., as the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc. Examples thereof include starch, agar, powdered gelatin, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, etc. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, Hardened vegetable oils and the like are allowed to be added to pharmaceuticals as coloring agents, but as flavoring agents, cocoa powder, peppermint, aromatic acid, peppermint oil, dragon brain, cinnamon powder, etc. It is needed. Of course, these tablets and granules may be sugar-coated, gelatin-coated, or any other suitable coating if necessary.

When preparing injectables, pH adjusters, solubilizers, suspending agents, buffers, stabilizers, preservatives, etc. are added to the main drug as necessary, and subcutaneous, intramuscular, intravenous For injection.

Next, typical formulation examples of the present invention are listed.

Formulation Example 1 Tablet Formulation Compound A 5 g Corn starch 10 g Purified sucrose 20 g Carboxymethylcellulose calcium 10 g Microcrystalline cellulose 40 g Polyvinylpyrrolidone 5 g Tar 10 g Total amount 100 g Compound A is dissolved in acetone, which is then dissolved in microcrystalline cellulose. After adsorption, it was dried. Corn starch, purified sucrose, and carboxymethylcellulose calcium were mixed with this, and then an aqueous solution of polyvinylpyrrolidone was added as a binder to granulate by a conventional method. Talc was added as a lubricant to this and mixed, and then compressed into tablets of 100 mg each.

Formulation example 2. Capsule compound B 5 g Microcrystalline cellulose 80 g Corn starch 20 g Lactose 22 g Polyvinylpyrrolidone 3 g Total amount 130 g The above components were granulated by a conventional method and then filled into a gelatin hard capsule.

Formulation Example 3 Powder compound C 50 g Microcrystalline cellulose 400 g Corn starch 550 g Total amount 1,000 g Compound C was dissolved in acetone, and this was adsorbed on microcrystalline cellulose and then dried. This was mixed with corn starch and made into a powder by a conventional method.

Formulation Example 4 Injectable compound D 10 g Nikkol HCO-60 37 g Sesame oil 2 g Sodium chloride 9 g Propylene glycol 40 g Phosphorus buffer (0.1 M, pH 6.0) 100 ml Distilled water Total amount 1,000 ml Compound D, Nikkol HCO-60, sesame oil And half of propylene glycol are mixed and dissolved by heating at about 80 ° C, and phosphate buffer solution and distilled water in which sodium chloride and propylene glycol are pre-dissolved are heated at about 80 ° C and added to make a total amount of 1. Made up to 000 ml of aqueous solution. This aqueous solution was dispensed into a 1 ml ampoule, melted, and then heat sterilized.

In addition, the production example of the compound of the present invention is shown for reference.

Production Example 1 5- (7-carboxy-3-methyl-2,6-octadienyl) -2,3,4-trimethoxy-6-methylphenol 2,3,4-trimethoxy-6-methylphenol 5 g was added to benzene 10 ml. Dissolve and add 10 g of silica alumina. To this solution, 1.8 g of 8-hydroxy-2,6-dimethyl-2,6-octadienoic acid was dissolved in 4 ml of benzene and added. This solution was heated to 40 to 50 ° C. and reacted for 2 hours. The reaction mixture was passed through, washed with ethyl ether, washed with water, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (eluting solvent ether-n-hexane mixed solution) to obtain 1.3 g of the title compound as a colorless oily substance.

Production Example 2 5- (11-carboxy-3,7-dimethyl-2,6,10
-Dodecatrienyl) -2,3,4-trimethoxy-6
5 g of -methylphenol 2,3,4-trimethoxy-6-methylphenol was dissolved in 10 ml of benzene, and silica gel (Wakogel C-20
6) Add 6 g and 3 g of zinc chloride. Add 12 to this solution.
2,4 g of -hydroxy-2,6,10-trimethyl-2,6,10-dodecatrienoic acid ethyl ester dissolved in 5 ml of benzene were added. After reacting for 30 minutes at room temperature, the reaction mixture was filtered, the residue was washed with ethyl ether, the solution was washed with water, dried over anhydrous magnesium sulfate and concentrated. Dissolve the concentrate in 50 ml of ethanol, add 3 g of potassium hydroxide,
After refluxing for 30 minutes, the solution was poured into diluted hydrochloric acid water and extracted with ethyl acetate. The extract was washed with water, dried (anhydrous magnesium sulfate), concentrated, and purified by silica gel chromatography (eluting solvent: ethyl acetate-benzene mixture) to obtain 1.7 g of the title target substance as a colorless oily substance.

Production Example 3 5- (15-carboxy-3,7,11-trimethyl-2,
6,10,14-hexadecatetraenyl) -2,3,4-
5 g of trimethoxy-6-methylphenol 2,3,4-trimethoxy-6-methylphenol was dissolved in 10 ml of benzene, and the solution was dissolved in silica gel (Wakogel C-20
6) Add 6 g and 3 g of zinc chloride. 16-
3 g of hydroxy-2,6,10,14-tetramethyl-2,6,10,14-hexadecatetraenoic acid dissolved in 5 ml of benzene were added. After reacting for 30 minutes at room temperature, the reaction mixture was filtered, the excess was washed with ethyl ether, the solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by silica gel chromatography (elution solvent: ether-n-hexane solution) to obtain 2.1 g of the title compound as a colorless oily substance.

Production Example 4 5- (19-carboxy-3,7,11,15-tetramethyl-2,6,10,14,18-eicosapentaenyl) -2,
3,4-trimethoxy-6-methylphenol 2,3,4-trimethoxy-6-methylphenol 5 g and 2
0-hydroxy-2,6,10,14,18-pentamethyl-2,6,10,
By a method similar to that in Production Example 1, starting with 3.2 g of 14,18-eicosapentaenoic acid as a starting material, the title compound as a colorless oil was obtained.
8 g was obtained.

Production Example 5 5- (23-carboxy-3,7,11,15,19-pentamethyl-2,6,10,14,18,22-tetracosahexaenyl) -2,3,4-trimethoxy-6- Methylphenol 2,3,4-trimethoxy-6-methylphenol 5g, 2
4-hydroxy-2,6,10,14,18,22-hexamethyl-2,6,
Using 3.5 g of 10,14,18,22-tetracosahexaenoic acid as a starting material and in the same manner as in Production Example 1, 2.5 g of the title compound was obtained as a colorless oil.

Production Example 6 5- (7-carboxy-3-methyl-2,6-octadienyl) -2,3-dimethoxy-6-methyl-1,4-
Benzoquinone 5- (7-carboxy-3-obtained according to Example 1
2 g of methyl-2,6-octadienyl) 2,3,4-trimethoxy-6-methylphenol was dissolved in 20 ml of ethyl acetate, 5 g of ferric chloride hexahydrate was added, and the mixture was allowed to stand at room temperature for 3 times.
Stir for 0 minutes. Add 100 ml of ether, wash with water, dry (anhydrous magnesium sulfate) and concentrate. The concentrate was purified by silica gel chromatography (eluting solvent: ethyl acetate-benzene mixed solution) to obtain 1.8 g of the title compound as an orange oil.

Production Example 7 5- (11-carboxy-3,7-dimethyl-2,6,10
-Dodecatrienyl) -2,3-dimethoxy-6-methyl-1,4-penzoquinone 5- (11-carboxy-3, obtained by Example 2
7-dimethyl-2,6,10-dodecatrienyl) -2,
1.5 g of 3,4-trimethoxy-6-methylphenol
In the same manner as in Production Example 6 using as the starting material, 1.4 g of the title compound was obtained as an orange oil.

Production Example 8 5- (15-carboxy-3,7,11-trimethyl-2,
6,10,14-Hexadecatetraenyl) -2,3-dimethoxy-6-methyl-1,4-benzoquinone 5- (15-carboxy-3, obtained by Preparation Example 3
By the same method as in Preparation Example 6 using 2 g of 7,11-trimethyl-2,6,10,14-hexadecatetraenyl) -2,3,4-trimethoxy-6-methylphenol as a starting material, an orange oily title. 1.7 g of compound was obtained.

Production Example 9 5- (19-carboxy-3,7,11,15-tetramethyl-2,6,10,14,18-eicosapentaenyl-2,3
-Dimethoxy-6-methyl-1,4-benzoquinone 5- (19-carboxy-3, obtained according to Preparation Example 4
7,11,15-Tetramethyl-2,6,10,14,18-eicosapentaenyl) -2,3,4-trimethoxy-6-
2.2 g of the orange title compound was obtained in the same manner as in Production Example 6 using 2.5 g of methylphenol as a starting material.

Production Example 10 5- (23-carboxy-3,7,11,15,19-pentamethyl-2,6,10,14,18,22-tetracosahexaenyl) -2,3-dimethoxy-6-methyl- 1,4-benzoquinone 5- (23-carboxy-3, obtained by Preparation Example 5
7,11,15,19-pentamethyl-2,6,10,14,18,
In the same manner as in Production Example 6, starting from 1.3 g of 22-tetracosahexaenyl) -2,3,4-trimethoxy-6-methylphenol, 1.1 g of the orange title compound was prepared.
Got

Next, Table 3 shows the physical properties of the compounds of the present invention obtained in Production Examples 1 to 5, and Table 4 shows the physical properties of the compounds of the present invention obtained in Production Examples 6 to 10.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroshi Suzuki 2-15 Toyo-cho, Showa-ku, Nagoya-shi, Aichi Nagoya University Toyo-cho Dormitory B-21 (72) Inventor Yoshiharu Shimomura 2-Higashizakura, Higashi-ku, Nagoya-shi, Aichi 18-3 Coop Nomura Higashizakura 1403 (72) Inventor Isao Yamazu 3605-669 Kashida, Ushiku-cho, Inashiki-gun, Ibaraki Prefecture 605-266 (72) Shinya Abe 40-2 (72) Shiroyama, Kashizaki-cho, Inashiki-gun, Ibaraki Prefecture Koji Yamada Ibaraki 5-8-8 Kariya, Ushiku-cho, Inashiki-ken, Japan (72) Toru Fujimori 2-9-9 Tokodai, Toyosato-cho, Tsukuba-gun, Ibaraki Prefecture (72) Innovator Tadano Takamura 1-10-28 Chiyoda, Naka-ku, Nagoya-shi, Aichi 1 B Highness Yabacho 202 (56) Reference JP-A-56-7737 (JP, A) JP-A-60-116657 (JP, A) JP-A-60-255749 (JP, A)

Claims (1)

[Claims] 1. A general formula [Where A is the expression Or a group represented by (Wherein X and Y mean the same or different hydroxyl groups or methoxy groups). n is 1
A quinone derivative represented by the formula [5] and a pharmacologically acceptable salt thereof as an active ingredient.