JPS624227A - Medicinal drug containing quinone derivative as active component - Google Patents

Abstract

PURPOSE:To provide a medicinal drug containing a quinone derivative and its salt as active component and having phospholipase-inhibiting action and anti-platelet action. CONSTITUTION:A medicinal drug useful as an anti-platelet agent, antithrombotic agent and remedy for various cardiac diseases can be produced by using a quinone compound of formula I [A is group of formula II or formula III (X and Y are OH, methoxy or H); n is 1-5] having carboxyl group at the terminal of polyprenyl chain and its salt. It is effective for the remedy and prevention of cerebrovascular disorder such as TIA (transient ischemic attack), cerebral infarction, cerebral arteriosclerosis, etc., various thrombosis, blood flow disorder and various inflammatory diseases such as rheumatic diseases. A compound of formula I wherein the group A is group of formula III can be produced by condensing the compound of formula IV with the compound of formula V (R is H or lower alkyl) in the presence of a catalyst.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a medicament containing a quinone derivative as an active ingredient. Let me explain in more detail.

The general formula means a group represented by the same or different hydroxyl group, methoxy group or hydrogen atom.

n means an integer of 1 to 5] The present invention relates to a quinone derivative represented by the following formula and a pharmaceutical containing a pharmacologically acceptable salt thereof as an active ingredient.

Ubidecarenone (also known as Coenzyme Qlo, U
Biquino-nolo is a substance isolated in crystal form from bovine heart muscle mitochondria by Crane et al. in 1957. It is widely distributed in living organisms, and is particularly abundant in mitochondria within cells, which is an energy-producing system. It is an important component of the mitochondrial electron transport chain.

The present invention has been intensively researching these derivatives of ubidecarenone for many years, and it has been discovered that a group of compounds having a carboxyl group at the end of the polyprenyl chain in the structure of f7 decarenone have excellent physiological activity.1 The present invention completed.

That is, the two compounds of the present invention mean a group represented by the general formula (I) (meaning the same or different hydroxyl group, methoxy group, or hydrogen atom).

(n means an integer from 1 to 5) This is a quinone compound having a carboxyl group in a wide polyprenyl chain.

The compounds of the present invention have extremely excellent phospholipase inhibitory and antiplatelet effects, and are useful as therapeutic agents based on these effects, such as antiplatelet agents, antithrombotic agents, and therapeutic agents for various heart diseases. Specifically, TIA (transient ischemic attack), cerebral infarction (thrombus, embolism), cerebrovascular disorders such as cerebral arteriosclerosis, various embolisms such as pulmonary embolism, vascular surgery, and extracorporeal blood treatment. Postoperative thrombi and emboli associated with circulation and blood flow disorders, Buerger's disease, arteriosclerosis obliterans, S
Improvement of congestive heart failure accompanied by peripheral blood flow disorder, edema, pulmonary congestion, liver swelling, etc. due to occlusion or stenosis of limb arteries such as collagen disease such as LE or white wax disease.

Treatment and prevention of heart diseases such as angina pectoris and myocardial infarction, pancreatitis, DIC (disseminated intravascular coagulation syndrome), and vascular disorders such as fundus vascular lesions due to diabetes, as well as prevention of recurrence and improvement of prognosis of these diseases. etc. can be given.

Furthermore, the compounds of the present invention are also effective in treating and preventing inflammatory diseases such as various rheumatic diseases.

The compound of the present invention can be produced by a variety of methods.One representative method is as follows.

(In the formula, X and Y are the same or different hydroxyl groups.

In the case of a group represented by a methoxy group or a hydrogen atom).

(In the formula, n means an integer of 1 to 5, and R means a hydrogen atom or a lower alkyl group.) That is, compound (II) and compound (ill) are mixed with a catalyst such as silica alumina or silica gel-zinc chloride. One of the target substances (I'
). In Formula 9 (■), when R is a lower alkyl group, it is hydrolyzed with caustic potash, caustic soda, etc. to form a carboxylic acid, which is designated as (I').

Manufacturing method 2 In the case of a group represented by (I') (wherein X, Y, and n have the above meanings) That is, compound (■') is converted into 9, for example, ferric oxide.

By treating with an oxidizing agent such as lead oxide, a benzoquinone compound represented by compound (■'), which is one of the target substances, can be obtained.

Next, experimental examples will be presented to explain in detail the effects of the compounds of the present invention.

Experimental Example 1 Inhibitory effect of phospholipase A (1) Experimental method Myristic acid liberated by phospholipase A was quantified by high performance liquid chromatography using Simyristile lecithin as a substrate.

Before quantifying the activity of the enzyme mentioned above, the test compounds shown below were added at the concentrations shown in Table 1 below, and their effects were investigated.

In addition, CoQ is used as a comparative example. was used.

Compound A: Compound B: Compound C: n Compound D= The results are shown in Table 1. Note that the values in Table 1 are based on 1
The numerical value of the test compound is shown when it is set to 00.

Phospholipase A, exhibits inhibitory action.

Table 1 From Table 1 above, it is clear that the compounds of the present invention have a significant phospholipase A inhibitory effect compared to CoQ,o.

Experimental Example 2 Antiplatelet effect on human platelets The compound of the present invention has an inhibitory effect on human platelet aggregation.
Examined in vitro. Platelet aggregation is caused by PAF (pl
Atelet activating factor-
...-1-alkyl-2-acetyl-3n-glycero-3-phosphocholine).

Experiments were conducted using collagen and ADP as inducers in the following manner.

(1) Platelet suspended plasma (PRP-...-platele)
Preparation of 1 volume of 3.8% sodium citrate solution to 9 volumes of blood was collected from the brachial vein of a healthy adult male.

The blood is centrifuged for 18 min at 100% P
RP was fractionated.

(2) Measurement of platelet aggregation 25 pl of sample solutions of various concentrations were added to PRP O, 2jut prepared by the above method, and incubated at 37°C for 3 minutes for 1n.
cubate and add the above inducer solution 25 to this.
μl was added to induce aggregation. As an inducer.

PAF 1100n/mt, :) Ragen 1pg/
ml, ADP 51 tM was added at a final concentration. Platelet aggregation was performed using agrogo manufactured by Bingen Biosciences.
The method of Mustard et al. [Mustard et al.
rd, J.F., Hegaldt, B., R.
owseuH-C,, MacMiuan, R,C,J.
, Lab, Clin, Med, 64, 548
-559 (1964):].

The inhibitory effect of the test compound is determined by the vehicle.
The agglomeration ability of the added layer was used as a control, and the evaluation was made based on the inhibition rate.

(3) The test compounds are as follows.

Compounds A to D are as shown in Experimental Example 1.

Compound E: Compound F: (4) The results are shown in Table 2.

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

From Table 2, two compounds of the present invention have +CoQ. It is clear that it has a superior antiplatelet effect compared to the antiplatelet effect.

Table 2 (Part 1) Next, the toxicity of the compounds of the present invention will be described.

Toxicity Experiments Acute toxicity experiments were conducted using the compounds of the present invention A-J and ddY male mice (weight 25-30 g), and all showed LD when administered orally. is 500 m9/
It was more than 'ss. In addition, when the compounds A-J of the present invention were injected through the tail vein of the mice (10 mice), 1011 g
7kg30Q/l? , 100xy/ky Regardless of the dose number ζ, the survival rate was 100% at 10/10.
(Therefore, LDSo is 1100JI/1w or more).

A medicament based on the phospholipase inhibitory effect of the compound of the present invention,
Medicines based on antiplatelet action 1ζ 2 For example, specifically, when used as various antiplatelet agents, antithrombotic agents, therapeutic agents for heart disease, and agents for the treatment and prevention of inflammatory diseases such as rheumatic diseases, oral administration or Administered orally (intramuscularly, subcutaneously, intravenously, suppositories, etc.). The dosage varies depending on the disease, symptoms, age of the patient, etc., but it is usually about toot to 1,0OOQ per day for adults, preferably about 50 s.
ty ~500 I11? It is.

In order to formulate a compound of the present invention, it is formed into a dosage form such as a tablet, granule, powder, capsule, injection, suppository, etc. by a conventional method in the field of pharmaceutical preparation.

That is, when preparing oral solid preparations, excipients are added to the crude drug, and binders and disintegrants are added as necessary.

Lubricants 9 After adding coloring agents, flavoring agents, etc., the mixture is prepared into tablets, coated tablets, granules, powders, capsules, etc. by conventional methods.

Examples of excipients include lactose and cornstarch.

White sugar, glucose, sorbitol, crystalline cellulose, etc.
As a binder, for example, polyvinyl alcohol, =te
9 Vinyl ether, ethyl cellulose.

Methylcellulose, gum arabic, tragacanth.

Gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc., and disintegrants include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, etc. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc.9 Colorants that are permitted to be added to pharmaceuticals are used as flavoring agents.

Cocoa powder, peppermint, aromatic acid, peppermint oil, cybernetic acid.

Cinnamon powder etc. are used. Of course, these tablets and granules may be coated with sugar coating, gelatin coating, or other coatings as appropriate.

When preparing injections, add pH adjusters, solubilizers, suspending agents, buffers, stabilizers, preservatives, etc. to the main drug as necessary, and administer subcutaneously, intramuscularly, or intravenously using conventional methods. As an internal injection.

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

Formulation Example 1 Tablet Compound A 5.9 Corn Starch 10I Refined White Sugar
20. t9 carboxymethyl cellulose calcium 10F! microcrystalline cellulose
40.9 Polyvinylpyrrolidone
511 tarri
10Ii all
Amount: 10011 Compound A was dissolved in acetone and then adsorbed onto microcrystalline cellulose, followed by drying. This includes corn starch, refined white sugar,
Carboxymethylcellulose calcium was mixed thereinto, an aqueous solution of polyvinylpyrrolidone was added as a binder, and the mixture was granulated by a conventional method. Talc was added as a lubricant to this, mixed, and then tableted into 100 tablets.

Compound B 5JF microcrystalline cellulose 80g corn starch 20/lactose
22g total amount
130I The above ingredients were granulated by a conventional method and then filled into hard gelatin capsules 1ζ.

Formulation Example 3 Powder Compound 0 50g Microcrystalline cellulose 400g Corn starch
550g total amount 1
,000. P compound C was dissolved in acetone and then adsorbed onto microcrystalline cellulose, followed by drying. This was mixed with corn starch and powdered and bound by a conventional method.

Formulation Example 4 Injection Compound D Io, 9Nik
kol HCO-6037El Sesame oil 2I Sodium chloride 9! I Propylene Glycol 40,9 Phosphate Buffer (0,IM
, pH 6,0) l Q Q ml distilled water
Total amount: 1,000 liters of compound, N1
Mix KKOL HCO-60, sesame oil and half the amount of propylene glycol, heat and dissolve at about 80°C, add phosphate buffer, sodium chloride and propylene glycol in distilled water and heat to about 80°C. In addition,
All fils were made into an aqueous solution of 0OOIR/. This aqueous solution was dispensed into 1 tnl ampoules, sealed, and sterilized by heating.

For reference, production examples of nine compounds of the present invention are shown below.

Production example 1 2,3,4-trimethoxy-5-methylphenol 5I
was dissolved in 1Qtnl of benzene, and 1゜I of silica alumina was dissolved in 1Qtnl of benzene.
Add. Add 1.8# of 8-hydroxy-2,6-dimethyl-2,6-octadiene It to this solution and add 4ml of benzene.
1 and added. This solution was heated to 40-50°C and reacted for 2 hours. Filter the reaction mixture.

After washing the filtrate with ethyl ether and washing the P solution with water.

It was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel chromatography (eluent: ether-n-
1.3 g of the title compound as a colorless oil (hexane mixture)
I got it.

Production Example 2 2,3.4-)dimethoxy-5-methylphenol 5
g is dissolved in 1 Qrnl of benzene, and 6 g of silica gel (Wako Gel C-200) and 3 g of zinc chloride are added.

To this solution was added 2.41 liters of 2-hydroxy-2,6,10-)dimethyl-2,6,10-)' decatrienoic acid ethyl ester dissolved in 5IR/J of benzene. After reacting for 30 minutes at room temperature, the reaction mixture was filtered, the filtrate was washed with ethyl ether, and the P solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated. Dissolve the concentrate in 50 Illl of ethanol and add 3 ml of caustic potash. Add i.

After refluxing for 30 minutes, the solution was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried (anhydrous magnesium sulfate), concentrated, and purified using silica gel chromatography. Elution solvent: ethyl acetate-benzene mixture) The title target substance was obtained as a colorless oil.1. 'l got it.

Production Example 3 2,3.4-)dimethoxy-5-methylphenol 5
Dissolve 6.9 g of benzene in 1 Qij of benzene, and add 6.9 g of silica gel (Wafugel C-200) and 3 I of zinc chloride.

To this syneresis, 16-hydroxy-2,6,10,14-tetramethyl-2,6,10,14-hexadecatetraenoic acid 3I dissolved in 5 ml of benzene was added. After reacting at room temperature for 30 minutes, the reaction mixture was filtered, the filtered product was washed with ethyl ether, and the P 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 the title compound 2.11 as a colorless oil.

Production Example 4 King 2,3.4-)dimethoxy-5-methylphenol 5
I and 20-hydroxy-2,6,10,14,18-
Using 3.21 of pentamethyl-2,6,10,14,18-eicosapentaenoic acid as a starting material, the title compound 2.8I as a colorless oil was obtained in the same manner as in Production Example 1.

Production Example 5 Phenol 2,3.4-)dimethoxy-5-methylphenol 5
1 and 24-hydroxy-2,6,10,14,18,
227 Hexamethyl-2.6.10.14.18.22
The title compound 2.51 as a colorless oil was obtained in the same manner as in Production Example 1 using 3.5 g of -tetracosahexaenoic acid as a starting material.

Production Example 6 6-(7-carboxy-3-
methyl-2,6-octagenyl) -2,3゜4-trimethoxy-5-methylphenol (2 g) and ethyl acetate (2 g)
Dissolve in 0 ml, add ferric chloride hexahydrate 5I,
Stir for 30 minutes at room temperature. Add 100 ml of ether, wash with water, dry (anhydrous magnesium sulfate) and concentrate. The concentrate was purified by silica gel chromatography (elution solvent: ethyl acetate-benzene mixture).

1.8 g of the title compound as an orange oil was obtained.

Production Example 7 Monomethyl-1,4-benzoquinone 6-(11-carboxy-
3,7-dimethyl-2.6.10-dodecatrienyl)
-2,3,4-) Dimethoxy-5-methylphenol 1.51 as the starting material, in the same manner as in Production Example 6,
The title compound 1.41 was obtained as an orange oil.

Production Example 8 6-(15-carboxy-3 obtained by Production Example 3)
,7,11-)dimethyl-2,6,10,14-hexadecatetraenyl)-2,3,4-)dimethoxy-5
The title compound 1.7I as an orange oil was obtained in the same manner as in Production Example 6 using -methylphenol 2I as a starting material.

Production Example 9 6-(19-carboxy-3,7,11,15-tetramethyl-2,6,10,14,18-eicosapentaenyl)-2.3-dimethoxy-5-methyl-1,4 -6-(19-carboxy-
3,7,11,15-tetramethyl-2,6,10,1
Using 2.5 fI of 4,18-eicosapentaenyl)-2,3,4-)dimethoxy-5-methylphenol as the starting material, the orange title compound 2.
I got 21.

Production Example 10 6-(23-carboxy-
3,7,11,15,19-pentamethyl-2,6,1
0,14゜18.22-tetracosahexaenyl)-2
,3,4-)dimethoxy-5-methylphenol 1.3
Using 1 as a starting material, 1.1 g of the orange title compound was obtained in the same manner as in Production Example 6.

Next, Table 3 shows the physical properties of the compounds of the present invention obtained in Production Examples 1 to 54, and Table 4 shows the physical properties of the compounds of the present invention obtained in Production Examples 6 to 1o.

Claims (1)

[Claims] 1. General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, A is a group or formula represented by the formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ There is▼(
In the formula, X and Y are the same or different hydroxyl group, methoxy group or hydrogen atom). n means an integer of 1 to 5] A medicament based on phospholipase inhibitory action containing a quinone derivative represented by the following and a pharmacologically acceptable salt thereof as an active ingredient. 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, A is a group or formula represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ There are mathematical formulas, chemical formulas, tables, etc. ▼ (
In the formula, X and Y are the same or different hydroxyl group, methoxy group or hydrogen atom). n means an integer of 1 to 5.] A medicament based on antiplatelet action containing a quinone derivative represented by the following and a pharmacologically acceptable salt thereof as an active ingredient. 3 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, A is a group or formula represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ There are mathematical formulas, chemical formulas, tables, etc. ▼ (
In the formula, X and Y are the same or different hydroxyl group, methoxy group or hydrogen atom). n means an integer of 1 to 5] A therapeutic/preventive agent for heart disease containing a quinone derivative represented by and a pharmacologically acceptable salt thereof as an active ingredient