JPH1067653A - Therapeutic agent for arthropathy - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare the subject agent, having high clinical effectiveness and high safety, nearly basically treating arthropathy and useful for treating chronic articular rheumatism, etc., by including a specific quinone derivative as an active ingredient therein. SOLUTION: This therapeutic agent comprises a quinone derivative represented by formula I [(n) is 0 or 1-12; R is methyl or methoxy] or its pharmacologically permissible salt, preferably (E)-3-[2-(5,6-dimethoxy-3-methyl-1,4- benzoquinonyl)]-2-nonylpropenoic acid (II) as an active ingredient). For example, the therapeutic agent is preferably administered in 0.01-200mg clinical dose to an adult according to peroral administration, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an agent for preventing / treating / ameliorating arthritis associated with arthritis, more preferably for preventing / treating / ameliorating rheumatoid arthritis, which has excellent action as a medicament.

[0002]

BACKGROUND OF THE INVENTION Joint diseases are broadly classified into osteoarthritis associated with degenerative degeneration or traumatic changes due to aging, polyarthritis associated with connective tissue disease, and monoarticular / polyarthritis of unknown origin. A typical example of connective tissue arthritis is rheumatoid arthritis. Although these arthrosis and arthritis do not directly lead to death, they cause pain due to the progression of cartilage and bone destruction over time and cause limb dysfunction, which is a disease that greatly affects daily life. is there.

[0003]

2. Description of the Related Art The treatment of rheumatoid arthritis and other arthritis varies depending on the degree and progress. For mild or early cases, non-steroidal anti-inflammatory drugs (NSAIDs) are used to reduce pain, and corticosteroids are used for moderate or more severe cases. In particular, for connective tissue disease arthritis such as rheumatoid arthritis, disease-modifying antirheumatic drugs (hereinafter, DMARDs: including immunosuppressants) are administered. In moderate to severe cases, a plurality of these drugs are often administered depending on the symptoms.

More specifically, as a typical example of NSAIDs,
For example, aspirin, ibuprofen, loxoprofen, diclofenac, indomethacin, etc., which have relatively short blood half-lives, naproxen, sulindac, fenbufen, diflunisal, etc., intermediate ones, and piroxicam, oxaprozin, tenoxicam, etc., which have long blood half-lives And the like. Representative examples of DMARDs include, for example, gold preparations, D-penicillamine, bucillamine, lobenzarit, sulfasalazine, actarit, immunosuppressants (mizoribine, methotrexate, azathioprine, cyclophosphamide, cyclosporine, etc.). Representative examples of corticosteroids include, for example, betamethasone, prednisolone,
Dexamethasone and the like can be mentioned.

[0005]

[Problems to be solved by the present invention] However, it is thought that immunological abnormalities are largely involved in the pathogenesis of joint diseases accompanied by arthritis such as rheumatoid arthritis, but there are still many unknown parts, and At present there is no cure. Currently used treatments are mainly symptomatic treatments, and it is difficult to suppress the progress of joint destruction which is the biggest problem of arthritis. Currently, seven formulations of injection gold (sodium gold thiomalate), oral gold (auranofin), D-penicillamine, lobenzarit, bucillamine, mizoribine and actarit are approved for rheumatoid arthritis. In some patients, joint destruction was suppressed to some extent, but there were many ineffective cases, and it was impossible to give satisfactory treatment to all patients.

[0006] Furthermore, NSAIDs have a very high frequency of gastrointestinal side effects such as gastric ulcers, side effects such as hepato-renal disorders and central nervous system disorders (anxiety, insomnia, drowsiness, etc.). Inspection was necessary, and long-term continuous use had many problems.

[0007] Regarding DMARDs, there are many ineffective cases, and it takes 3 to 4 months to develop the effect, and even if it is a mild case, there is a problem that the lesion progresses during that time. Further, even in effective cases, an escape phenomenon in which the effect diminishes two to three years after use may occur, and the side effects such as rash, interstitial pneumonia, renal disorder, and hematopoietic disorder are also common problems.

[0008] Corticosteroids (betamethasone, prednisolone, dexamethasone, etc.), when administered for a long period of time, have a number of side effects such as induction of infections due to reduced immunity, endocrine abnormalities, pigmentation on the skin, and bone porosity. And long-term administration required careful observation.

As described above, at present, there are no fundamental remedies for joint diseases such as arthritis and rheumatoid arthritis, and there are many safety problems, and new preventive, therapeutic and ameliorating agents are required. Had been.

[0010]

Means for Solving the Problems The present inventors have conducted various studies in order to develop a therapeutic agent for arthritis such as rheumatoid arthritis, which is highly clinically effective, close to fundamental treatment, and highly safe. I have piled up. As a result, they have found that the quinone derivative (I) represented by the following general formula achieves the intended purpose, and completed the present invention. The quinone derivative (I) according to the present invention has a great feature of having excellent anti-arthritic action and safety, and the value of the present invention is extremely high.
Here, the quinone derivative (I) according to the present invention is represented by the following general formula.

[0011]

Embedded image

In the formula, n represents 0 or an integer of 1 to 12, and R represents a methyl group or a methoxy group. The quinone derivative (I) according to the present invention has a double bond in the molecule and has geometric isomers, but is not limited in the present invention, and any single isomer (E isomer) Or a Z isomer) or a mixture of two or more (EZ mixture). May also form hydrates

The pharmacologically acceptable salt in the present invention is not limited as long as it forms an addition salt with the quinone derivative (I) according to the present invention.
Examples thereof include addition salts of alkali metals such as sodium salt, potassium salt and lithium salt, addition salts of alkaline earth metals such as magnesium salt and calcium salt, addition salts of amines, and addition salts of amino acids.

Here, more specific examples of the quinone derivative (I) include the following compounds, but the present invention is not limited thereto.

(1) 3- [2- (5,6-dimethoxy-3-methyl-1,4-
Benzoquinonyl)] propenoic acid (2) 3- [2- (5,6-dimethoxy-3-methyl-1,4-benzoquinonyl)]-2-propylpropenoic acid (3) 3- [2- (5,6- Dimethoxy-3-methyl-1,4-benzoquinonyl)]-2-hexylpropenoic acid (4) 3- [2- (5,6-dimethoxy-3-methyl-1,4-benzoquinonyl)]-2-nonylpropene Acid (5) 3- [2- (5,6-dimethoxy-3-methyl-1,4-benzoquinonyl)]-2-dodecylpropenoic acid (6) 3- [2- (3,5,6-trimethyl- 1,4-benzoquinonyl)] propenoic acid (7) 3- [2- (3,5,6-trimethyl-1,4-benzoquinonyl)]-2-
Propylpropenoic acid (8) 3- [2- (3,5,6-trimethyl-1,4-benzoquinonyl)]-2-
Hexylpropenoic acid (9) 3- [2- (3,5,6-trimethyl-1,4-benzoquinonyl)]-2-
Nonylpropenoic acid (10) 3- [2- (3,5,6-trimethyl-1,4-benzoquinonyl)]-2
-Dodecylpropenoic acid

Among these quinone derivatives (I), more preferred is 3- [2- (5,6-dimethoxy-3-methyl-1,4-benzoquinonyl)]-2-nonylpropenoic acid, and further preferred is (E) -3- [2- (5,6-dimethoxy-3- represented by the following chemical formula:
Methyl-1,4-benzoquinonyl)]-2-nonylpropenoic acid (II)
Can be mentioned.

[0017]

Embedded image

The quinone derivative (I) according to the present invention
Can be produced according to the method described in JP-A-3-18842.

Next, the dosage form of the compound of the present invention includes, for example, oral preparations such as powders, fine granules, granules, tablets, coated tablets and capsules, external preparations such as ointments and patches, suppositories and creams , Lotions and injectable preparations.
At the time of formulation, it can be produced by a conventional method using a usual pharmaceutical carrier.

That is, in order to produce an oral preparation, the compound of the present invention and an excipient and, if necessary, an antioxidant, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent and the like are added. Powders, fine granules, granules, tablets, coated tablets, capsules and the like are prepared by a conventional method.

Examples of the excipient include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and the like.
For example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol polyoxyethylene block polymer, meglumine, etc. For example, starch, agar, gelatin powder,
Crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethylcellulose / calcium, etc., as lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc., coloring agents As a flavoring agent, cocoa powder, peppermint brain, aromasan, peppermint oil, dragon brain, cinnamon powder and the like are used as flavoring agents. Of course, these tablets and granules can be sugar-coated and optionally coated as needed.

In preparing an injection preparation, a pH adjuster, a solubilizer, an isotonic agent and the like, and if necessary, a solubilizer, a stabilizer, an antioxidant and the like are added to the compound of the present invention. hand,
It is formulated by the usual method.

The method for producing the external preparation is not limited.
It can be manufactured by an ordinary method. In other words, base materials used in the formulation include pharmaceuticals, quasi-drugs,
Various raw materials usually used for cosmetics and the like can be used.

Specific examples of base materials used include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, and polyhydric acids. Raw materials such as alcohols, water-soluble polymers, clay minerals, purified water, etc. are added, and if necessary, pH adjusters, antioxidants, chelating agents, antiseptic / antifungal agents, coloring agents, fragrances, etc. are added. However, the base material of the external preparation according to the present invention is not limited to these. If necessary, components such as a blood flow promoter, a bactericide, an anti-inflammatory agent, a cell activator, vitamins, amino acids, a humectant, a keratolytic agent, and the like can be added. The amount of the base material to be added is an amount that usually results in a concentration set in the production of an external preparation.

The clinical dose of the quinone derivative (I) or a pharmacologically acceptable salt thereof according to the present invention depends on the condition, severity, age, complications, etc., and is not limited. It is usually 0.01 mg to 2000 mg per adult day, preferably 0.1 mg to 1
000 mg, more preferably 1 mg to 500 mg, which is administered orally, intravenously, intramuscularly, rectally or transdermally.

[0026]

[Effects of the Invention]
In order to show the usefulness as an improver, pharmacological experimental examples and toxicity test examples are listed below as effect examples, but it goes without saying that the compounds of the present invention or uses are not limited thereto.

Examples of Pharmacological Experiments (Experimental Methods) The test compounds include (E) -3- [2- (5,6-dimethoxy-3-) as a typical example of the quinone derivative (I) according to the present invention.
Methyl-1,4-benzoquinonyl)]-2-nonylpropenoic acid [hereinafter, compound (I)], and prednisolone (Prednisolone) as a positive control.

(1) Grouping of Animals Forty-five 6-7 week old F344 male rats, which were preliminarily bred for 1 to 2 weeks, were divided into six groups by a random method as shown in the following table. No Group No.Test compound dose Number of subjects ──────────────── ──────────1 Control 0.5% methylcellulose (10 ml / kg) 8 2 Compound (I) 10 mg / kg 8 3 Compound (I) 30 mg / kg 8 4 Compound (I) 100 mg / kg 8 5 Prednisolone 5 mg / kg 8 6 Untreated 8 ──────────────────────────

(2) Administration Method and Conditions Each administration sample was prepared by the following method. 1) Control (0.5% methylcellulose solution) 5 g of methylcellulose was weighed, dissolved in 800 ml of distilled water, and the volume was increased to 1000 ml. The prepared 0.5% methylcellulose solution was dispensed in approximately 200 ml at a time, sealed and sealed at 121 ° C for 15 minutes.
And sterilized and stored at room temperature. After opening, it was stored at 4 ° C.

2) Compound (I) 300-600 mg of compound (I) was placed in a mortar and suspended while adding a 0.5% methylcellulose solution little by little. This suspension was messed up with 0.5% methylcellulose solution, and 10
It was adjusted to be 0 mg / ml. The 100 mg / ml solution was diluted with 0.5% methylcellulose solution as shown in the table below to prepare 30 and 1 mg / ml suspensions. ───────────────────────── Suspension concentration: undiluted solution + 0.5% methylcellulose solution ────────────── ─────────── A 50 (mg / ml)-B 15 A solution 15-20 ml + 7/3 volume of added solution A C 5 A solution 4-6 ml + 9 times of added solution B Volume に A is in group No. 4 (100 mg / kg), suspension B is in group No. 3 (30 mg / kg) /kg)
, Suspension C was administered to group No. 2 (10 mg / kg). 4 in suspension
The stability at 1 ° C. for one week was separately confirmed and stored at 4 ° C. for one week. Those after one week were discarded, and a new suspension was prepared.

3) Prednisolone 40 to 60 mg of Prednisolone was placed in a mortar and suspended while adding a 0.5% methylcellulose solution little by little. This suspension was messed up with a 0.5% methylcellulose solution,
It was adjusted to 1 mg / ml. The stability of the suspension at 4 ° C for one week was separately confirmed, and the suspension was stored at 4 ° C for one week. Those after one week were discarded, and a new suspension was prepared.

Each test compound was suspended in 0.5% methylcellulose to prepare suspensions of each concentration.
kg was orally administered orally using a stainless steel oral probe.

(3) Preparation of adjuvant and induction of arthritis 1) Preparation of adjuvant Take 100 mg of bovine lactic acid bacteria (Mycobacterium butyricum) in a mortar,
After crushing well, 10 ml of liquid paraffin was added and mixed well, followed by autoclaving (120 ° C., 20 minutes).

2) Induction of arthritis The adjuvant prepared as described above was injected into the right hind footpad of a rat in an amount of 50 μl to induce arthritis.

(4) Experimental Schedule The day after the completion of the repeated administration, blood was collected and the spleen, thoracic line and adrenal gland were removed. Various hematology using the collected blood,
Inflammatory parameters were evaluated and each organ was weighed.

(5) Pretreatment of animals Before blood collection, anesthesia was performed with ether.

(6) Experimental procedure 1) Measurement items a) Hematological parameters: hematocrit value, hemoglobin content, red blood cell count and white blood cell count b) Inflammatory parameters: red blood cell sedimentation rate, albumin to globulin ratio, sialic acid content and Plasma fibrinogen content c) Organ weight 2) Sampling and preparation a) Blood sampling The abdomen is opened under ether anesthesia to expose the abdominal aorta. Immediately after blood collection, EDTA blood collection tube, 250% 3.8% sodium citrate solution
1, 2, and 2 ml each were dispensed into plastic tubes (Yamanouchi Pharmaceutical, Tokyo) and glass test tubes containing μl.
After about 5 ml of blood was collected from the abdominal aorta and dispensed into each test tube, the blood and the anticoagulant were mixed in the test tube. b) Organ sampling After blood collection, the spleen, thoracic line and adrenal gland were excised and weighed to calculate the weight per body weight.

3) Experimental method a) Measurement of hind limb volume The hind limb volume was measured using a rat hind limb footpad edema volume measuring device TK-1 (Unicom), and the rate of increase in volume was determined by the following equation. The normal value was a value measured immediately before injection of the adjuvant in the treated foot, and the value measured 7 days after injection (immediately before the onset of the secondary inflammation) in the untreated foot. Volume increase rate = (measured value-normal value) / (normal value) b) Hematocrit value, hemoglobin amount, red blood cell count and white blood cell count Comprehensive hematology analyzer H-1 (Techinicon Instruments Cro
p., U.S.A.), the red blood cell count in EDTA-2K-supplemented blood (two-angle laser scattered light detection method), the average red blood cell volume (MC
V, two-angle laser scattered light detection method), platelet count (two-angle laser scattered light detection method), white blood cell count (enzyme staining absorbance scattered light quantity classification method), and hematocrit value (HCT)
The mean erythrocyte hemoglobin concentration (MCHC) was calculated. c) The ratio of albumin to globulin, the amount of sialic acid and the amount of plasma fibrinogen were measured by Koto Microbiological Research Institute (Tsukuba City). d) Erythrocyte sedimentation rate Take a well-mixed 3.8% sodium citrate solution in a plastic tube into a 2.5 ml injection syringe (Terumo), and inject 1 ml into the blood sedimentation tube (Nichipet C, Nippon Clinical Machinery Co., Ltd., Tokyo). did. Thereafter, the erythrocyte sedimentation distance was measured 1 hour and 2 hours later, and the erythrocyte sedimentation velocity was used. e) Measurement of blood interleukin 6 (IL-6) It was measured by a bioassay using B9 (cells that grow in an IL-6-dependent manner). Serum was serially diluted in a 96-well plate from 10-fold to 2-fold in 7 steps. Using human recombinant IL-6 as a standard, a standard curve was prepared by diluting 9 units in two steps from 5 units / ml. 1500 B9 / 50μ in 50μl of sample
l was added to each well and cultured in a CO ₂ incubator for 3 days. After that, MTT was added to PBS (Phosphate-buffered salin
e) was dissolved at a rate of 5 mg / ml, and 20 μl was added to each well. One hour later, 100% of 10% SDS (Sodium lauryl sulfate) was added to each well and dissolved, and then measured at two wavelengths of 540 and 660 nm using a microplate reader, and the IL-6 value was calculated from the value obtained by subtracting the latter. .

4) Measuring instrument Comprehensive hematology analyzer H-1 (Techinicon Instruments Co.,
USA) Microplate Reader NJ-2000 (Nippon Intermed Co., Ltd., Tokyo) Rat limb footpad edema volume measuring device TK-1 (Unicom, US
A.)

(Results) All are shown as mean ± standard error.

[0041]

In the group administered with Compound (I) 100 mg / kg, a clear inhibitory effect on edema was observed. On the last day (day 21), the compound
(I) An inhibitory effect was also observed in the 30 mg / kg administration group.
(See FIGS. 1 and 2)

3) IL-6 (see FIG. 10) Test compound ──────────────── Compound (I) [mg / Kg] Prednisolone control 10 30 100 5 Untreated ───────────────── ──────── 4.268 4.162 2.660 1.775 1.809 0 ± 0.656 ± 0.831 ± 0.889 ± 0.282 ± 0.253 ± 0 ──────────────────────── ─

Further, compound (I) also shows an inhibitory effect on the inflammatory cytokine IL-6 in a dose-dependent manner, and in particular, the 100 mg / kg group shows almost the same inhibition as the prednisolone 5 mg / kg group. Was. (See Fig. 10)

In addition, no clear inhibitory action was shown for acute phase reaction proteins such as fibrinogen.
Regarding blood sedimentation, although there was a tendency of suppression, there was no significant difference.

From the above results, it is clear that the compounds of the present invention have excellent preventive, therapeutic and ameliorating effects on joint diseases.

Example of Toxicity Test (Experimental Method) As a test compound, (E) -3- [2- (5,6-dimethoxy-3-methyl-1,4-benzoquinonyl)]-2-nonylpropenoic acid [compound ( I)] was used. (1) Rats A test compound of 250, 500, 1000, and 2000 mg / Kg was forcibly administered once to each of three males and females of one group of SD rats and observed for 14 days. The test compound was administered once by gavage at 10, 20, and 60 (20 / hour x 3) mg / Kg to 5 males and 5 females per group of SD rats and observed for 14 days. (2) Beagle dog In addition, 100, 200, 400 mg / Kg of the test compound was
A single gavage was administered to one male and one female in each group and observed for 21 days.

(Results) The following table shows lethal doses of rats and beagle dogs after a single administration.

[0049]

From the above table, the excellent safety of the compound of the present invention is apparent.

[Brief description of the drawings]

FIG. 1 shows a group administered with a compound of the present invention and a positive control group (Prednisol
1 is a graph showing the time-dependent changes in the volume increase rate of the treated paw in one group and the control group. (Mean ± standard error)

FIG. 2 shows a group administered with the compound of the present invention and a positive control group (Prednisol
1 is a graph showing the time-dependent change in the rate of volume increase of untreated feet in one and control groups. (Mean ± standard error)

FIG. 3 shows a compound administration group of the present invention and a positive control group (Prednisol
It is the graph which compared the thymus weight in one) and a control group. (Mean ± standard error)

FIG. 4 shows a compound administration group of the present invention and a positive control group (Prednisol
It is the graph which compared the sialic acid amount in one) and a control group. (Mean ± standard error)

FIG. 5 shows a compound administration group of the present invention and a positive control group (Prednisol
It is a graph which compared A / G ratio in one) and a control group.
(Mean ± standard error)

FIG. 6 shows a group administered with the compound of the present invention and a positive control group (Prednisol
It is a graph which compared the blood sediment in one) and a control group.
(Mean ± standard error)

FIG. 7 shows a compound administration group of the present invention and a positive control group (Prednisol
It is a graph which compared the peripheral erythrocyte count in one) and a control group. (Mean ± standard error)

FIG. 8 shows a compound administration group of the present invention and a positive control group (Prednisol
It is the graph which compared spleen weight in one) and a control group. (Mean ± standard error)

FIG. 9 shows a compound administration group of the present invention and a positive control group (Prednisol
1 is a graph comparing the amount of fibrinogen in one group and a control group. (Mean ± standard error)

FIG. 10 shows a group administered with the compound of the present invention and a positive control group (Prednis
9 is a graph comparing IL-6 in a control group with olone).
(Mean ± standard error)

Claims (4)

[Claims] 1. A quinone derivative (I) represented by the following general formula:
Or a preventive, therapeutic, or ameliorating agent for arthritis-related joint disease comprising a pharmacologically acceptable salt thereof as an active ingredient. Embedded image (In the formula, n represents 0 or an integer of 1 to 12, and R represents a methyl group or a methoxy group.) 2. The preventive, therapeutic or ameliorating agent for joint disease according to claim 1, wherein the joint disease associated with arthritis is rheumatoid arthritis. Embedded image (In the formula, n and R have the same meanings as described above.) 3. The quinone derivative (I) represented by the following chemical formula: (E) -3- [2- (5,6-dimethoxy-3-methyl-1,4-benzoquinonyl)]-2-nonylpropenoic acid The agent for preventing, treating or improving arthritis associated with arthritis according to claim 1, which is (II). Embedded image 4. A quinone derivative (I) represented by the following chemical formula: (E) -3- [2- (5,6-dimethoxy-3-methyl-1,4-benzoquinonyl)]-2-nonylpropenoic acid The agent for preventing, treating or improving rheumatoid arthritis according to claim 2, which is (II). Embedded image