JPH1171275A - Therapeutic medicine for rheumatism comprising nonsteroidal anti-inflammatory agent and phenylpropionic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To find out new usability of 3-[1-[6-(4-methoxyphenyl)hexa-5E- enyl]oxy-3-(4-carboxylbutyl)oxybenzen-2-yl]propionic acid. SOLUTION: This therapeutic agent for rheumatism comprises a combination of a nonsteroidal anti-inflammatory agent and 3-[1-[6-(4-methoxyphenyl)hexa-5E- enyl]oxy-3-(4-carboxylbutyl)oxybenzen-2-yl]propionic acid or its salt. Both ingredients of the combination mutually complement and/or enhances their actions. The nonsteroidal anti-inflammatory agent is preferably diclofenac or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a nonsteroidal anti-inflammatory drug and 3- [1- [6- (4-methoxyphenyl) hexa-5E-enyl] oxy-3- (4-carboxylbutyl) oxybenzene- 2-yl] propionic acid or a combination thereof with a therapeutic agent for rheumatism.

[0002]

2. Description of the Related Art Rheumatism is an intractable chronic inflammatory disease mainly involving the synovium of the joint, but its cause is often unknown and its symptoms are various. One of the features of the pathology of rheumatism is abnormal growth of the synovium and subsequent destruction of cartilage and bone. The main treatment of rheumatism is pharmacotherapy, but steroids and nonsteroidal anti-inflammatory drugs have been used for a long time to cure inflammation of rheumatism, and immunity is involved in rheumatism in recent years. , Immunosuppressants, immunomodulators (DMARDs)
Etc. have been used. In addition, for the purpose of compensating for each of the disadvantages and making use of the merits, studies using combinations of drugs have been attempted.

Recently, research on drugs based on a new mechanism of action has been actively conducted. Leukotriene B ₄ (LT
B ₄₎ it is also one of the antagonists. 5 derived from arachidonic acid
- LTB ₄ is a metabolite of lipoxygenase system, it plays an important role in leukocyte function are known to have an inducing inflammation effects. Specifically, it has strong migration, chemotaxis, aggregation, production and release of active oxygen to leukocytes, and acts on vascular endothelium to enhance the adhesion of leukocytes to vascular endothelial cells. . On the other hand, L
TB ₄ has increased in rheumatic patients synovial fluid, in cultured synovial cells from rheumatic patients, has been reported to promote interleukin-1 production (rheumatism, 31, 762 (1991)). Further, by decreasing the LTB ₄ content, there is a report showing that improve rheumatism and inflammatory bowel disease, etc. (Exp. Opin. Invest.Drugs, 5 , 73-7
7 (1996)).

[0004] 3- [1- [6-] represented by the following formula [I]
(4-methoxyphenyl) hex-5E-enyl] oxy-3- (4-carboxylbutyl) oxybenzene-
2-yl] propionic acid (hereinafter referred to as the present compound)
It has LTB ₄ antagonistic activity and is useful for prevention and / or treatment of various diseases such as allergic dermatitis, rheumatism, gout, psoriasis, arthritis, tinea, myocardial infarction, etc.
No. 39369. Further, the compound that competitively inhibit receptor binding of LTB ₄ on human neutrophils (Prostaglandins, 44, 261-275 (1982 )), also reported to exhibit immunosuppressive effect on liver allograft in rats (Surg. Today, 26 , 419-426 (1996)
).

[0005]

Embedded image

[0006] In addition, various studies have been made on combinations of LTB ₄ receptor antagonists with other drugs. For example, the effect of a combination of a cycloalkyl carboxylic acid derivative and a nonsteroidal anti-inflammatory drug on collagen-induced arthritis (Arthritis Rheum., 39 515-521 (199)
6)), benzopyran derivative and cyclooxygenase-2
Effect on collagen-induced arthritis by combination with an inhibitor (WO 96/41645), Effect on mating asthmatic rats by combination of a pyridine-substituted benzyl alcohol derivative and a nonsteroidal anti-inflammatory drug (Table 7-) 505401).

[0007] However, there has been no report on the effect of the combination of the present compound with a nonsteroidal anti-inflammatory drug.

[0008]

SUMMARY OF THE INVENTION The present compound, which has not only an LTB ₄ receptor antagonistic effect but also an immunosuppressive effect, in combination with a non-steroidal anti-inflammatory drug, has found a new usefulness. It was a very interesting task.

[0009]

Means for Solving the Problems The present inventors have focused on the treatment of rheumatism and have intensively studied the effects of the combination of the present compound with a nonsteroidal anti-inflammatory drug. Various methods have been reported for examining the effects on rheumatism using animal models. For example, a method using a collagen-induced arthritis model (Nature, 283 , 666-668 (1980),
roc. Natl. Acad. Sci. USA., 92 , 517-521 (1995)),
Method using an adjuvant-induced arthritis model (Ann. Rhe
um.Dis., 15 379-380 (1956), Br. J. Pharamacol., 2
1 , 127-136 (1963)). Moreover, rheumatism is accompanied by joint inflammation and edema, and a method of study using a zymosan-induced foot edema model as an acute inflammation model is also known (Agents Actions, 32 , 119-121 (1991)).
Therefore, in the present invention, the effect on rheumatism was examined using these animal models. Detailed test methods and results will be described in Examples (pharmacological tests) described below. By combining the non-steroidal anti-inflammatory drug with the present compound, a remarkable inhibitory effect is exhibited on those models. Was. Moreover, the effects were synergistic, and were completely unexpected from the effects of the nonsteroidal anti-inflammatory drug and the compound alone. These results clearly show that the combination of the present compound with a nonsteroidal anti-inflammatory drug is very useful as a therapeutic agent for rheumatism. Further, the therapeutic agent for rheumatism according to the present invention can be suitably used not only for the treatment but also for the prevention of rheumatism.

[0010]

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a non-steroidal anti-inflammatory drug and 3- [1- [6- (4-methoxyphenyl) hexa-5E-enyl] oxy-3- (4-carboxybutyl) oxybenzene. -2-yl] propionic acid (the present compound) or a combination thereof with a salt thereof, more specifically, a therapeutic agent for rheumatism characterized by complementing and / or enhancing the action of each other. is there.

In the treatment of rheumatism, the non-steroidal anti-inflammatory agent and the present compound may be administered in the form of a single preparation, or may be administered in separate preparations, that is, in the form of combined administration.

The compound may be in the form of a salt.
The salts in the present invention are not particularly limited as long as they are pharmaceutically acceptable salts, salts with inorganic acids such as hydrochloric acid, nitric acid and sulfuric acid, and alkali metals or alkaline earth metals such as sodium, potassium and calcium. And ammonium salts, salts with organic amines such as diethylamine and triethanolamine salts. The compound may be in the form of a hydrate.

The present invention is characterized in that a therapeutic agent for rheumatism is obtained by combining a nonsteroidal anti-inflammatory agent with the present compound. The present invention is not limited to the type of nonsteroidal anti-inflammatory agent. Absent. In the present invention, known non-steroidal anti-inflammatory agents can be used. For example, diclofenac, loxoprofen, ketoprofen, ibuprofen, naproxen, indomethacin, piroxicam and the like are exemplified. These drugs include sodium salts,
Some salts are actually used in the form of salts, but the salts are omitted here unless otherwise specified. Further, the nonsteroidal anti-inflammatory drug which can be used in the present invention includes those in the form of a so-called prodrug.

The preparation for carrying out the present invention may be a preparation in which a non-steroidal anti-inflammatory agent and the present compound are blended, or a preparation in which each component is separately prepared. No special technique is required for the preparation of these preparations, and the preparation may be prepared using commonly used techniques. Dosage forms include tablets, capsules, powders, granules,
Examples include a local injection, an external solution, a liniment, and the like, and the administration is performed by systemic administration or local administration.

When the nonsteroidal anti-inflammatory agent and the present compound are separately prepared, they can be prepared according to a known method. For example, as a preparation of the present compound,
No. 9369 can be used as a non-steroidal anti-inflammatory agent, and a commercially available preparation can be used. In the case of a preparation containing a nonsteroidal anti-inflammatory agent and the present compound, the preparation can be prepared in the same manner as described above according to a known method. For example, tablets, capsules, powders, in the case of solids such as granules, lactose, crystalline cellulose, bulking agents such as starch, magnesium stearate, lubricants such as talc, hydroxypropylcellulose, polyvinylpyrrolidone and the like Binder, carboxymethylcellulose
Calcium, disintegrators such as low-substituted hydroxypropylmethylcellulose, hydroxypropylmethylcellulose,
It can be prepared by using a coating agent such as macrogol or silicone resin as needed.

For reference, some of the preparation examples are described in the following Examples (formulation examples), but of course the preparation examples do not limit the scope of the present invention.

The dosage of the nonsteroidal anti-inflammatory drug and the present compound is determined according to the patient's condition, age and the like.
The dose of the compound is usually 1 to 1000 per day.
In the range of mg, it is administered once or in several divided doses. Preferably, the daily dose is 10-500 mg, more preferably 50-300 mg. The dose of the non-steroidal anti-inflammatory drug varies depending on the type of the drug, but is usually determined based on the dose in the range actually used as the anti-inflammatory drug, and is appropriately increased or decreased depending on symptoms and the like.
The daily dose is in the range of 1 to 1000 mg and is administered once or in several divided doses. Preferably the daily dose is between 10 and 600 mg. More specifically, in the case of diclofenac sodium, a daily dose of 75 to
100 mg is usually used, but the dose may be appropriately adjusted depending on the symptoms and the like. Other non-steroidal anti-inflammatory drugs may be determined based on similar criteria. These dosages may be appropriately increased or decreased depending on the dosage form. These dosages are applied when the present compound and a non-steroidal anti-inflammatory agent are administered in combination. Is prepared by appropriately selecting the blending ratio such that the above-mentioned dosage is the above-mentioned amount, and the blended formulation is administered once or several times a day.

Hereinafter, pharmacological tests and preparation examples will be shown as examples, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.

[0019]

【Example】

[Pharmacological Test] 1) While the action type II collagen-induced arthritis model for type II collagen-induced arthritis is widely used as animal models of disease of rheumatism, report of study of the inhibitory effect of LTB ₄ receptor antagonists using the model Natl. Acad. Sci. USA., 92 , 517-521 (199
Five) ).

Therefore, the effect of the present compound in combination with a nonsteroidal anti-inflammatory drug on type II collagen-induced arthritis was examined according to the method described in the above-mentioned literature.

(Experimental Method) An emulsion was prepared by mixing a dilute hydrochloric acid solution of bovine articular cartilage-derived type II collagen (4 mg / ml) and an equal amount of Freund's complete adjuvant. As a primary sensitization, 100 µl of this emulsion (type II collagen:
200 μg / mouse). 2 from primary sensitization
One day later, the emulsion was applied again in the skin at the base of the mouse ridge.
00 μl was injected (secondary sensitization).

A suspension of the test compound prepared so as to give a dose of 10 ml per kg of body weight (this compound is 0.5
% Carboxymethylcellulose suspension and 1% methylcellulose suspension for non-steroidal anti-inflammatory drugs) were orally administered continuously once a day from the day before the first sensitization.

Regarding the onset of arthritis, the onset of arthritis was determined when swelling of the joint site with erythema was observed. In addition, the degree of arthritis was scored for each limb according to the following evaluation criteria for the degree of arthritis, and the total score of the four limbs was used as the arthritis score.

[Evaluation criteria for degree of arthritis] No change ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 0 ・ Weak swelling and weak erythema are observed ‥‥‥‥‥ 1 ・ Weak swelling Erythema is observed. ‥‥‥‥‥‥‥ 2 · Strong swelling and erythema are observed. ３ 3 · Strong swelling and erythema with bone deformation are observed. ‥ 4 26 after secondary sensitization On the day, radiographs of the four limb joints were taken. Observation under a microscope, scoring was performed for each limb according to the following evaluation criteria for the degree of bone destruction, and the total score of the four limbs was used as a bone destruction score.

[Evaluation criteria for the degree of bone destruction] No change ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 0 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ Bone destruction is recognized in one finger ‥‥‥‥‥‥‥‥ 1・ Bone destruction is observed in two or more fingers. ‥‥‥‥‥‥ 2 ・ Bone destruction is observed in all joints. ３3 (Results) As an example of the experimental results, the compound (100 mg) was used.
/ Kg) and diclofenac sodium (3 mg / kg), which is a non-steroidal anti-inflammatory agent, are shown in FIG.
The bone destruction score is shown in FIG.

For comparison, administration of the compound alone (10
0 mg / kg, 200 mg / kg), the results of diclofenac sodium alone administration (3 mg / kg), and the non-administration of the test compound (control) are also shown in FIGS. 1 to 3.

First, as shown in FIGS. 1 and 2, the onset of arthritis was observed in the control group on day 3 after the secondary sensitization, and in all cases on day 7 after the secondary sensitization. Was observed. Thereafter, the state of arthritis continued to worsen until day 21 after the second sensitization.

The compound of the present invention 100
In the combined administration group of mg / kg and diclofenac sodium 3 mg / kg, no onset of arthritis was observed up to 14 days after the secondary sensitization, and a significant delay effect of the onset of arthritis was observed. The arthritis score also improved significantly,
No strong swelling with erythema was observed up to 19 days after the next sensitization.

However, 100 mg / kg of the present compound
In the single administration group, a slight improvement in the arthritis score was observed, but the incidence of arthritis showed only a similar transition to the control group. This tendency is to reduce the dose by 2
It did not change even when it was increased to 00 mg / kg.

Further, diclofenac sodium 3 mg /
In the group administered with kg alone, an improvement in the arthritis score was observed, but the effect of delaying the onset of arthritis was not observed.

Next, the effect of suppressing bone destruction is shown in FIG.
In the combined administration group of 100 mg / kg of the present compound and 3 mg / kg of diclofenac sodium, a remarkable effect of inhibiting bone destruction was observed as compared with the control group. On the other hand, in the group administered with 100 mg / kg of the present compound alone, no inhibitory effect was observed at all, and almost no inhibitory effect was observed even when the dose was increased to 200 mg / kg. In the diclofenac sodium 3 mg / kg single administration group,
Although an inhibitory effect was observed, the effect was much weaker than in the case of co-administration.

From the above results, it can be seen that joint use of the present compound and a nonsteroidal anti-inflammatory agent significantly suppresses type II collagen-induced arthritis and bone destruction. It became clear that each of the nonsteroidal anti-inflammatory drugs was unexpectedly excellent from the effect of the single administration.

2) Effect on adjuvant-induced arthritis The adjuvant-induced arthritis model is a commonly used model for examining the effect of a drug on joints.
Therefore, the combined effect of the present compound and a nonsteroidal anti-inflammatory drug was examined using this model.

(Experimental method) Mycobacterium butyricum
(Adjuvant) liquid paraffin suspension (0.6 mg
/ 100 μl) was administered to a rat (male, 9 weeks old, weighing about 240).
g) was injected subcutaneously into the left hind footpad to induce arthritis. A suspension of a test compound prepared at a dose of 0.5 ml per 100 g body weight once a day from the 14th day after adjuvant injection (this compound is a 0.5% carboxymethylcellulose suspension, a nonsteroidal suspension) 1% methylcellulose suspension) was orally administered.

As a control, only a base containing no test compound was administered in the same manner as described above.

(Results) When arthritis is induced, edema is observed in the limb, and the limb volume increases. Therefore, the compound (1)
00 mg / kg) and diclofenac sodium (1 mg / kg) or loxoprofen (3 mg / kg) as a representative example of a non-steroidal anti-inflammatory agent, the left hind limb volume is shown in FIG. 4 and FIG. In addition, arthritis occurs throughout the body, and is delayed not only at the site of adjuvant administration but also at the right hind limb. The measurement results of the right hind limb volume are shown in FIG. 6 and FIG.

For comparison, the results of the present compound alone, the nonsteroidal anti-inflammatory agent alone, and the control group are also shown in the figures.

Further, after measuring the above test results, a histopathological examination was performed.

As shown in FIGS. 4 and 5, edema of the left hind limb caused by adjuvant injection is nearly steady on day 14. The edema was remarkably suppressed in the group administered with the present compound and a nonsteroidal anti-inflammatory drug.
On the other hand, the edema-suppressing effect was hardly observed in the group administered with the compound alone. The edema-suppressing effect was observed in the non-steroidal anti-inflammatory drug alone administration group, but the effect of the combination administration group was significantly superior. As shown in FIG. 6 and FIG. 7, edema appears on the right hind limb 10 days after adjuvant injection. When the volume of the right hind limb was measured, the same result as in the case of the left hind limb was obtained. These results
The synergistic effect of the combination of the compound and a non-steroidal anti-inflammatory agent is clearly shown.

In the histopathological examination, in the findings of bone destruction, edema and the like, the compound alone administration group and the nonsteroidal anti-inflammatory drug alone administration group showed almost no change suppressing effect. A clear effect was observed in the group administered with the compound and the nonsteroidal anti-inflammatory drug.

[0041] 3) acting arthritis for zymosan-induced paw edema is a disease involving inflammation, zymosan-induced paw edema model has been reported as an animal model to investigate the anti-inflammatory effect of LTB ₄ receptor antagonists (AgentsActions,
32 , 119-121 (1991)).

Therefore, the effect of the combination of the present compound and a nonsteroidal anti-inflammatory drug on zymosan-induced limb edema was examined in accordance with the method described in the above literature.

The experiment was performed by the following method.

Lipoedema was induced by injecting 100 μl of a zymosan physiological saline suspension (2%) subcutaneously into the left hind footpad of the rat. The volume was measured with a plethysmometer. The test compound was orally administered 1 hour before zymosan injection.

The effect of the test compound was determined using the amount of change in limb volume immediately before zymosan injection as an index.

As a result, in the group administered with the present compound and the nonsteroidal anti-inflammatory agent, a remarkable edema suppressing effect was observed as compared with the group administered with the present compound alone or the nonsteroidal anti-inflammatory agent alone.

[Formulation Example] The following components were mixed in a conventional manner, and then filled into capsules.

1) Diclofenac sodium 3 g The present compound 100 g Lactose 150 g

2) Diclofenac sodium 25 g The present compound 50 g Lactose 150 g

By appropriately changing the mixing ratio of each component,
A desired capsule can be prepared. Similar capsules can be prepared by using other non-steroidal anti-inflammatory drugs instead of diclofenac sodium.

[0051]

From the results of the above pharmacological tests, it has been found that a combination of the present compound or a salt thereof with a nonsteroidal anti-inflammatory drug is very useful for the treatment of rheumatism.

[Brief description of the drawings]

FIG. 1 is a graph showing the time course of arthritis incidence in type II collagen-induced arthritis in mice. In the graph, ◎ indicates 3- [1- [6- (4-methoxyphenyl)
Hexa-5E-enyl] oxy-3- (4-carboxylbutyl) oxybenzene-2-yl] propionic acid (the present compound) (100 mg / kg) and diclofenac sodium (3 mg / kg) (7 cases) Average value). .DELTA. And .quadrature. Show the results of the group administered with this compound alone (100 mg / kg, 200 mg / kg; average value of 9 cases). ○ indicates the results of the diclofenac sodium alone administration group (3 mg / kg; average value of 9 cases). ● shows the results of the test compound non-administration group (control group; average value of 9 cases).

FIG. 2 is a graph showing the daily change of arthritis score in type II collagen-induced arthritis in mice. In the graphs, は indicates the results of the combined administration group (the average value of 7 cases) of the present compound (100 mg / kg) and diclofenac sodium (3 mg / kg). .DELTA. And .quadrature. Show the results of the group administered with this compound alone (100 mg / kg, 200 mg / kg; average value of 9 cases). ○ indicates the results of the diclofenac sodium alone administration group (3 mg / kg; average value of 9 cases). ● indicates the test compound non-administration group (control group;
(Average of 9 cases).

FIG. 3 is a graph showing bone destruction scores in type II collagen-induced arthritis of mice. In the graph, A is a combined administration group of the present compound (100 mg / kg) and diclofenac sodium (3 mg / kg) (average value of 7 cases)
The result is shown. B and C are the groups administered the compound alone (10
0 mg / kg, 200 mg / kg; all of them are average values of 9 cases). D shows the results of the diclofenac sodium single administration group (3 mg / kg; average value of 9 cases).
E shows the results of the test compound non-administration group (control group; average value of 9 cases).

FIG. 4 is a graph showing the time course of the volume of the left hind limb in adjuvant-induced arthritis in rats. In the graph,
○ shows the results of the combined administration group of this compound (100 mg / kg) and diclofenac sodium (1 mg / kg) (average value of 7 cases). □ is the compound administered alone (100 m
g / kg) (average value of 8 cases). △ shows the result of the diclofenac sodium single administration group (1 mg / kg) (average value of 8 cases). ● indicates the results of the test compound non-administration group (control group, average value of 8 cases).

FIG. 5 is a graph showing the time course of the volume of the left hind limb in adjuvant-induced arthritis in rats. In the graph,
○ shows the results of the combined administration group of this compound (100 mg / kg) and loxoprofen (3 mg / kg) (average value of 8 cases). □ indicates the compound administered alone (100 mg / k
The result of g) is shown (average value of 8 cases). △ shows the result of the loxoprofen single administration group (3 mg / kg) (average value of 8 cases). ● is the test compound non-administration group (control group,
(Average of 8 cases).

FIG. 6 is a graph showing the time course of the volume of the right hind limb in adjuvant-induced arthritis in rats. In the graph,
○ shows the results of the combined administration group of this compound (100 mg / kg) and diclofenac sodium (1 mg / kg) (average value of 7 cases). □ is the compound administered alone (100 m
g / kg) (average value of 8 cases). △ shows the result of the diclofenac sodium single administration group (1 mg / kg) (average value of 8 cases). ● indicates the results of the test compound non-administration group (control group, average value of 8 cases).

FIG. 7 is a graph showing the time course of the volume of the right hind limb in adjuvant-induced arthritis in rats. In the graph,
○ shows the results of the combined administration group of this compound (100 mg / kg) and loxoprofen (3 mg / kg) (average value of 8 cases). □ indicates the compound administered alone (100 mg / k
The result of g) is shown (average value of 8 cases). △ shows the result of the loxoprofen single administration group (3 mg / kg) (average value of 8 cases). ● is the test compound non-administration group (control group,
(Average of 8 cases).

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor: Satoshi Matsuno 3-9-19-1 Shimoshinjo, Higashiyodogawa-ku, Osaka-shi, Osaka Inside Santen Pharmaceutical Research Laboratories (72) Yukifumi Fujisawa 3-9-1, Shimoshinjo, Higashiyodogawa-ku, Osaka-shi, Osaka No. Santen Pharmaceutical Research Laboratories (72) Masaaki Murai Inventor 3-9-1-19 Shimoshinjo, Higashiyodogawa-ku, Osaka-shi, Osaka No. Santan Pharmaceutical Research Laboratories (72) Nagamo Omiwa 3-1-1 Sakurai, Shimamotocho, Mishima-gun, Osaka Ono Pharmaceutical (72) Inventor Koichiro Terai 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka Ono Pharmaceutical Co., Ltd.

Claims (3)

[Claims] 1. A nonsteroidal anti-inflammatory agent and 3- [1-
A therapeutic agent for rheumatism comprising [6- (4-methoxyphenyl) hex-5E-enyl] oxy-3- (4-carboxylbutyl) oxybenzene-2-yl] propionic acid or a combination thereof. 2. A nonsteroidal anti-inflammatory agent and 3- [1-
[6- (4-methoxyphenyl) hexa-5E-enyl] oxy-3- (4-carboxylbutyl) oxybenzene-2-yl] propionic acid or a salt thereof, and complement and complement each other's actions. A therapeutic agent for rheumatism, characterized in that the agent enhances rheumatism. 3. The therapeutic agent for rheumatism according to claim 1, wherein the non-steroidal anti-inflammatory drug is diclofenac or a salt thereof.