HK1117050A - Preventive and/or therapeutic agent for rheumatoid arthritis - Google Patents

Description

Preventive and/or therapeutic agent for articular rheumatism

Technical Field

The present invention relates to a preventive and/or therapeutic agent for articular rheumatism.

Background

Articular rheumatism is a condition that causes inflammation accompanied by swelling and pain of multiple joints, and irreversible joint deformity and dysfunction occur over a long period of time, resulting in a significant decrease in Quality of Life (Quality of Life: QOL). In japan, there are patients corresponding to 0.6% of the population and 1% of the population over 30 years old, and particularly, in recent years, there is a tendency that patients with rheumatism in the elderly increase with a gradual shift to the elderly society.

Articular rheumatism can be divided into 4 stages: (1) in the initial stage: while there are symptoms of joint pain and arthritis, a period of definitive diagnosis of articular rheumatism has not been made; (2) early stage: although the joint rheumatism can be diagnosed definitely, the joint rheumatism is not changed irreversibly or is slightly changed even if the joint rheumatism is changed irreversibly (early joint rheumatism generally means 1 to 2 years after the disease); (3) the implementation period is as follows: the period of the occurrence of irreversible changes and obvious appearance of general symptoms such as fatigue, slight fever, weight loss and the like; (4) and (3) in the late stage: although the inflammatory condition of the joints hardly progresses, irreversible changes such as deformity and atrophy are seriously left, and pain and dysfunction become the main symptoms. The treatment method varies depending on the disease stage. Although research has been reported on the onset of articular rheumatism, genetic factors, acquired factors (infectious diseases), and the like, the cause of articular rheumatism is still not completely understood, and thus, the current situation is still incomplete in the cure and prevention of articular rheumatism. The present therapeutic aim is to diagnose articular rheumatism at an early stage, suppress inflammation of articular rheumatism as rapidly and as far as possible, prevent the occurrence of irreversible changes or arrest the progress thereof, and seek to improve QOL (quality of life) of patients in physical, mental, and social aspects. Therefore, in the treatment of articular rheumatism, various methods such as physiotherapy, exercise therapy, pharmacotherapy, and surgical therapy should be used in addition to the patient to be fully described about the disease and the treatment method thereof.

As the drug therapy, nonsteroidal (steroidal) anti-inflammatory drugs (NSAIDs), pain-relieving antirheumatic drugs (DMARDs: disease-modifying anti-inflammatory drugs), steroid drugs, and the like are clinically used. Recently, biological agents such as antibodies targeting inflammatory cytokines (cytokines) have also been used (see non-patent document 1).

NSAIDs are used as synonyms for cyclooxgenase (cox) inhibitors. Most of the agents belonging to this category have COX inhibitory activity. As for COX, two isoforms (isotype) of COX1 and COX2 are known at the gene level. In recent years, COX3, which is a variant of COX1, has been discovered (see non-patent document 2). COX inhibitors are formulated for patients with articular rheumatism, and are mainly intended to have an analgesic effect with quick action, but have little effect of relieving articular rheumatism itself. However, because DMARDs for relieving articular rheumatism have a delayed effect, it is common to increase QOL (quality of life) of patients with articular rheumatism before the DMARDs exert an effect, and to use COX inhibitors. Based on the above background, although COX inhibitors are prescribed for most patients with articular rheumatism, conventional COX inhibitors (e.g., indomethacin (indomethacin), aspirin) having both COX1 inhibitory action and COX2 inhibitory action can cause severe digestive tract failure in the stomach of a patient, and are regarded as a problem. Therefore, in recent years, COX2 selective inhibitors that cause less digestive tract troubles have been developed (see non-patent document 3). In addition, it has recently been confirmed that COX2 selective inhibitors also have a great side effect of increasing the risk of cardiovascular disease (see non-patent document 4). Thus, it becomes a situation where certain restrictions have to be taken for large dose use or long-term use of COX inhibitors.

It is known that Interleukin-1 β (IL-1 β) as an inflammatory cytokine has been confirmed to have an enhancing effect on many diseases such as articular rheumatism, osteoarthritis, osteoporosis, inflammatory colitis, immunodeficiency syndrome (immunodeficiency syndrome), sepsis, hepatitis, nephritis, ischemic diseases (ischemic disease), insulin-dependent diabetes, arteriosclerosis, parkinson's disease, Alzheimer's disease, and leukemia; and, it induces the synthesis of enzymes that are thought to be involved in inflammation such as collagenase (collagenase), COX and PLA 2; in addition, when injected into the joints of animals, joint destruction very similar to rheumatoid arthritis is incurred. Based on the above facts, an IL-1 β inhibitor has been studied and developed as a therapeutic agent for inflammatory diseases. Known examples of the low molecular weight compounds include substances derived from living organisms such as IL-1 receptor antagonists (refer to non-patent document 5), and low molecular weight compounds such as T-614 (refer to non-patent document 6), S-2474 (refer to non-patent document 7), 2-benzyl-5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -2H-pyridazin-3-one (2-benzyl-5- (4-chlorophenyl) -6- [4- (methythio) phenyl ] -2H-pyridazin-3-one) (refer to patent document 1), and FR133605 (refer to non-patent document 8).

The conditions of articular rheumatism vary considerably among patients in terms of age, stage of disease, complications, side effects, QOL, etc. Furthermore, there is no absolute therapeutic agent. There is also a phenomenon called "escape phenomenon" (that a therapeutic agent capable of controlling a disease suddenly loses efficacy on a certain day). In view of the above background, it is necessary to frequently replace or use a drug in combination with a drug therapy. Therefore, clinical studies on methods of using drugs are also prevalent.

Although there have been reports on agents having both COX2 inhibitory activity and IL-1 β inhibitory activity (see patent document 2 and non-patent documents 9 to 10), the effect of the combination of an agent having COX2 inhibitory activity and an agent having IL-1 β inhibitory activity, particularly the effect thereof on articular rheumatism, is not known.

Patent document 1: international publication No. 99/25697 pamphlet

Patent document 2: international publication No. 03/084936 pamphlet

Non-patent document 1: american College of Rheomatology on Rheomatomatoid Arthritis guidiness, Arthritis & Rheomatosis 46, pp328-346, 2002

Non-patent document 2: natl, Acad, Sci, USA, 99, pp13926-13931, 2002

Non-patent document 3: proc.Natl.Acad.Sci.USA.96, pp7563-7568, 1999

Non-patent document 4: N.ENGL.J.MED.351, pp1707-1711, 2004, Circulation 111, p249, 2005

Non-patent document 5: arthritis & Rheumatism 42, pp498-506, 1999

Non-patent document 6: Pharmacobio-Dyn.11, pp649-655, 1992

Non-patent document 7: YAKUGUKU ZASSHI 123, pp323-330, 2003

Non-patent document 8: rheumatol.23, pp1778-1783, 1996

Non-patent document 9: Jpn.J. Pharmacol.67, pp305-314, 1995

Non-patent document 10: Pharmacobio-Dyn.15, pp649-655, 1992

Disclosure of Invention

The purpose of the present invention is to provide a drug having an excellent effect of treating and preventing articular rheumatism.

The present inventors have made extensive studies in view of such circumstances, and have found that an excellent effect of inhibiting arthritis can be obtained when 2-benzyl-5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -2H-pyridazin-3-one as an IL-1. beta. inhibitor and an agent having COX2 inhibitory activity (COX2 inhibitor) are used in combination, thereby completing the present invention.

Namely: the present invention provides a preventive and/or therapeutic agent for articular rheumatism, which comprises 2-benzyl-5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -2H-pyridazin-3-one and a COX2 inhibitor.

Further, the present invention provides a method for treating articular rheumatism, which comprises administering effective amounts of 2-benzyl-5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -2H-pyridazin-3-one and COX2 inhibitor.

The present invention also provides the use of 2-benzyl-5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -2H-pyridazin-3-one and a COX2 inhibitor for the production of a preventive and/or therapeutic agent for articular rheumatism.

Effects of the invention

The preventive and/or therapeutic agent for articular rheumatism of the present invention can be orally administered, shows a small side effect and an excellent effect of inhibiting arthritis, and is useful for the prevention and treatment of arthritis.

Drawings

All figures use the mean, standard error and numerical representation of the various embodiments.

FIG. 1 is a graph showing the Edema Index and inhibition rate of collagen-induced arthritis model in mice when 2-benzyl-5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -2H-pyridazin-3-one and diclofenac sodium (diclofenac sodium) were co-administered.

FIG. 2 is a graph showing the Edema Index and inhibition rate of collagen-induced arthritis model in mice when 2-benzyl-5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -2H-pyridazin-3-one and ketoprofen (ketoprofen) were administered in combination.

FIG. 3 is a graph showing the Edema Index and inhibition rate of collagen-induced arthritis model in mice when 2-benzyl-5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -2H-pyridazin-3-one and meloxicam (meloxicam) were co-administered.

FIG. 4 is a graph showing the Edema Index and inhibition rate of collagen-induced arthritis model in mice when 2-benzyl-5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -2H-pyridazin-3-one and celecoxib (celecoxib) were administered in combination.

Fig. 5 is a graph showing the Edema Index and the inhibition rate of a collagen-induced arthritis model in mice when the content of celecoxib in the prophylactic and/or therapeutic agent for articular rheumatism of the present invention is changed.

Detailed Description

2-benzyl-5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -2H-pyridazin-3-one (hereinafter, also referred to as agent A) used in the preventive and/or therapeutic agent for articular rheumatism of the present invention is a known substance. For example, the substance can be produced by the method described in International publication No. 99/25697 or other similar methods. Namely: 2- (4-chlorophenyl) -4' - (methylthio) acetophenone was prepared by reacting p-chlorophenylacetic acid with phenylthiomethane using a condensing agent (condensing agent) such as polyphosphoric acid. Ethyl 2- (4-chlorophenyl) -4- [4- (methylthio) phenyl ] -4-oxoacetoacetate (compound b) is obtained by reacting compound a with a base such as potassium tert-butoxide in tetrahydrofuran and then adding ethyl bromoacetate. Compound b is reacted with hydrazine (hydrazine) hydrate in ethanol to give 5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -4, 5-dihydro-2H-pyridazin-3-one (compound c). The compound c thus obtained is reacted with benzyl bromide in a solvent such as N, N-dimethylformamide using a base such as potassium carbonate to produce the agent a.

Examples of COX2 inhibitors used in the preventive and/or therapeutic agent for articular rheumatism of the present invention include COX2 inhibitors such as carboxylic acid-based, enolic acid-based, methanesulfonic acid-based, and tricyclic systems. Examples of the carboxylic acid COX2 inhibitor include salicylic acid inhibitors such as aspirin; an aminobenzoic acid system or a fenamic acid system such as mefenamic acid (mefenamic acid), flufenamic acid (flufenamic acid), tolfenamic acid (tolfenamic acid), and the like; phenylacetic acid series of diclofenac or its salt, alclofenac, fenbufen, nabumetone (nabumetone), and lumiracoxib (lumiracoxib); indolacetic acid systems such as indomethacin (indomethacin), sulindac (sulindac), indomethacin farnesyl (indomethacin farnesyl), proglumicin maleate (proglumicetamide), acemetacin (acemetacin), and amfenac (amfenac); heterocyclic acetic acid systems such as tolmetin (tolmetin); pyranoacetic acid (pyranoacetic acid) series such as etodolac (etodolac); propionic acid COX2 inhibitors such as ibuprofen (ibuprolofen), pranoprofen (pranoprofen), naproxen (naproxen), ketoprofen (ketoprofen) or a salt thereof, flurbiprofen (flurbiprofen), tiaprofen, pranoprofen (pranoprofen), loxoprofen (loxoprofen), oxaprozin (oxaprozin), alminoprofen (alminoprofen), and zaltoprofen (zaltoprofen).

The salt of diclofenac and the salt of ketoprofen are not particularly limited as long as they are pharmaceutically acceptable salts, and examples thereof include inorganic salts and organic salts such as sodium salts and potassium salts thereof.

Examples of the enolic acid-based COX2 inhibitor include pyrazolone-based compounds such as phenylbutazone, clofeprazone (clofenazone), Febrazone (Febrazone), and oxyphenbutazone (oxyphenylbutazone); COX2 inhibitors of oxicam (oxicam) system such as piroxicam (piroxicam), amobicum (ampiroxicam), tenoxicam (tenoxicam), lornoxicam (lornoxicam), and meloxicam. Examples of the methanesulfonic acid-based COX2 inhibitor include nimesulide (nimesulide), florosulide (florosulide), and T-614. Examples of tricyclic COX2 inhibitors include rofecoxib (rofecoxib), celecoxib, valdecoxib (valdecoxib), and etoricoxib (etoricoxib). In addition, when these compounds have optical activity, optical isomers thereof are also included. As COX2 inhibitors, carboxylic acid-based, enolic acid-based, tricyclic COX2 inhibitors are preferred; more preferably phenylacetic, propionic, oxicam (oxicam) and tricyclic COX2 inhibitors; diclofenac or a salt thereof, ketoprofen or a salt thereof, meloxicam, and celecoxib (hereinafter, also referred to as drug B in some cases) are particularly preferable. For these substances, commercially available products, for example, diclofenac and ketoprofen, manufactured by SIGMA company; for meloxicam, products manufactured by Wako pure chemical industries, Ltd; for celecoxib, a product manufactured by desynths s.a., or the like can be used.

The content of COX2 inhibitor in the agent for preventing and/or treating articular rheumatism of the present invention is preferably 1000: 1 to 1:30 in terms of the mass ratio (agent A: COX2 inhibitor). In the case of a carboxylic acid-based COX2 inhibitor, the ratio is more preferably 300: 1 to 1:3, and particularly preferably 100: 1 to 1: 1. In addition, in the case of an enolic acid-based tricyclic COX2 inhibitor, the ratio is particularly preferably 10: 1 to 3: 10.

The administration form of the preventive and/or therapeutic agent for articular rheumatism of the present invention is not particularly limited, and may be appropriately selected depending on the purpose of treatment, and examples thereof include oral administration such as tablets, capsules, granules, film-coated agents, powders and syrups, and non-oral administration such as injections, suppositories, inhalants, transdermal absorbents, eye drops and nasal drops. The preferred form of administration is oral.

The preventive and/or therapeutic agent for articular rheumatism of the present invention can be prepared into pharmaceutical preparations containing the agent a and the COX2 inhibitor as the active ingredients, and administered simultaneously or separately at set time intervals; it can also be administered as a pharmaceutical preparation containing both the active ingredients.

In these pharmaceutical preparations suitable for administration forms, pharmaceutically acceptable carriers such as excipients and extenders including starches, lactose, sucrose, mannitol, silicic acid, etc.; disintegrating agents such as agar, calcium carbonate (calcium carbonate), potato starch or tapioca starch, alginic acid (alginic acid), and complex silicate; a lubricant such as a binder such as hydroxypropyl methylcellulose, sodium carboxymethylcellulose, alginate (alginate), gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc., talc, calcium stearate, magnesium stearate, solidified polyethylene glycols, sodium lauryl sulfate, or a mixture thereof; diluents such as lactose, corn starch, etc.; buffers such as organic acids including citric acid, phosphoric acid, tartaric acid and lactic acid, inorganic acids including hydrochloric acid, alkali metal hydroxides including sodium hydroxide and potassium hydroxide, and organic amines including triethanolamine, diethanolamine and diisopropanolamine; preservatives such as parabens and benzalkonium chloride (benzalkonium chloride); emulsifiers such as anionic surfactants such as calcium stearate, magnesium stearate, and sodium lauryl sulfate, cationic surfactants such as benzalkonium chloride (benzalkonium chloride), benzethonium chloride (benzethonium chloride), and cetylpyridinium chloride (cetylpyridinium chloride), and nonionic surfactants such as glyceryl monostearate, sucrose fatty acid ester, polyoxyethylene hardened castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, and polyoxyethylene alkyl ether; stabilizers such as sodium sulfite, sodium hydrogen sulfite, dibutylhydroxytoluene (dibutylhydroxytoluene), butylated hydroxyanisole (butylhydroxytryanosole), and EDTA. In addition, a taste-improving agent, a dispersing agent, a preservative, a perfume and the like may be appropriately combined as necessary.

The dose of 2-benzyl-5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -2H-pyridazin-3-one of the present invention can be appropriately selected depending on the body weight, age, sex, disease condition, etc. of a patient. In the case of an ordinary adult, the daily dose may be 2 to 320mg, preferably 4 to 160 mg. The dose of COX2 inhibitor to be administered varies depending on the type thereof. In the case of an adult, the daily dose may be 1 to 1500 mg.

The dose of the carboxylic acid-based or enolic acid-based COX2 inhibitor varies depending on the type thereof. In the case of an adult, the daily dose may be 1 to 1500 mg. For example, when diclofenac is used, the daily dose may be 25 to 300mg, preferably 100 to 150 mg. In the case of using ketoprofen, the daily dose may be 25 to 400mg, preferably 100 to 300 mg. In addition, when meloxicam is used, the daily dose may be 1 to 50mg, preferably 5 to 20 mg.

The dose of the tricyclic COX2 inhibitor to be administered varies depending on the type thereof. In the case of an adult, the daily dose may be 10 to 1500 mg. For example, when celecoxib is used, the daily dose may be 100 to 800mg, preferably 200 to 400 mg.

Examples

The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to these examples.

Example 1

The effect of the combined administration of 2-benzyl-5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -2H-pyridazin-3-one (agent A) and diclofenac sodium (agent B-1), the combined administration of agent A and ketoprofen (agent B-2), the combined administration of agent A and meloxicam (agent B-3), the combined administration of agent A and celecoxib (agent B-4), and the individual administration of each, on the inhibition of edema in both hind limbs was determined according to the following model of collagen-induced arthritis in mice (FDA, CBER, CDER, CDRH: guide for index-Clinical resolution programs for drugs, devices, and biological products for the treatment of the hind limb inflammation (RA) - (1999)).

The test animals used female Lewis white mice (LEW/Crj) (Charles river laboratories Japan, Inc.).

The volume (volume of both hind limbs) from the ankle part to the toe part of both hind limbs of an LEW/Crj mouse aged 8 weeks was measured as the volume of both hind limbs at the start of the test (Pre value) using a foot volume measuring device for a small animal (TK-101CMP, manufactured by Unicom Co.). The Pre value is used as an index, one parameter is changed arbitrarily to divide the mice into a plurality of groups, and the groups are divided into groups with uniform quality.

A collagen emulsion (collagen emulsion) for Sensitization (Sensitization) to induce arthritis in white mice was prepared by uniformly mixing a liquid containing 0.3% type II collagen (manufactured by collagen research institute), an additive peptide (manufactured by peptide research), and an additive incorporated free (manufactured by DIFCO Co.) in ice-cold conditions using a manual Micro Homogenizer (Handy Micro Homogenizer) (manufactured by Microtection). The first sensitization was performed by injecting the prepared collagen emulsion into the skin at a ratio of 0.1mL/site in 10 sites on the back of a white mouse. 7 days after the first sensitization, 0.12mL of the same collagen emulsion was injected into the tail root of the mouse again intradermally, and additional sensitization was performed.

Administration was started up to 18 days after the first sensitization. The agent A and the agents B-1, B-2 and B-4 are orally administered for 2 times in the morning (9: 00-11: 00) and afternoon (15: 30-17: 30). In addition, the drug B-3 was orally administered 1 time at noon (11: 30-13: 30).

After 14 days and 18 days of the first sensitization, the volume of both hind limbs was measured again, and the difference between each of the volumes and the Pre value was calculated to calculate the volume of edema of both hind limbs. The sum of the volume of Edema of both hind limbs 14 days and 18 days after the first sensitization was calculated as the Edema Index, and this was used as an Index of drug efficacy.

Tables 1 to 4 and FIGS. 1 to 4 show the Edema Index of the drug A3mg/kg or 10mg/kg single administration group, the drug B11 mg/kg single administration group, the drug B20.3 mg/kg single administration group, the drug B30.2 mg/kg single administration group, the drug B41 mg/kg single administration group, and the two-drug combination administration group. The Edema Index is expressed as the mean. + -. standard error of 8 mice per group. The reduction ratio was represented by ((X-Y)/X). times.100 (X: the average value of the Edema indexes of the control group, and Y: the average value of the Edema indexes of the respective groups).

TABLE 1

Is tested for medicament	Edema Index	Reduction ratio (%)	Relative index
				Control group	3.66±0.11
Drug A3mg/kg single administration group	3.20±0.15	13	0.87
				Drug B-11mg/kg single administration group	1.20±0.26	67	0.33
Combination of drug A and drug B-1	0.33±0.05	91	0.09

Note 1) product of relative indices of the individual administration groups: 0.87 × 0.33 ═ 0.29.

Note 2) both hind limb edema volumes are expressed as mean ± standard error of 6 mice per group.

The drug A and the drug B-1 were combined, the Edema Index was greatly reduced, and the product of the relative indexes of the Edema Index was smaller than that of the drug A and the drug B-1, and it was confirmed that a significant synergistic effect was obtained by the combined administration.

TABLE 2

Is tested for medicament	Edema Index	Reduction ratio (%)	Relative index
				Control group	3.66±0.11
A3mg/kg single administration group	3.20±0.15	13	0.87
				Agent B-20.3mg/kg single administration group	1.08±0.35	71	0.29
Combination of drug A and drug B-2	0.62±0.13	83	0.17

Note 1) product of relative indices of the individual administration groups: 0.87 × 0.29 — 0.25.

Note 2) both hind limb edema volumes are expressed as mean ± standard error of 6 mice per group.

The drug A and the drug B-2 were combined, the Edema Index was greatly reduced, and the product of the relative indexes of the Edema Index was smaller than that of the drug A and the drug B-2, and it was confirmed that a significant synergistic effect was obtained by the combined administration.

TABLE 3

Is tested for medicament	Edema Index	Reduction ratio (%)	Relative index
				Control group	3.48±0.08
Drug A3mg/kg single administration group	3.00±0.18	14	0.86
				Agent B-30.2mg/kg single administration group	2.04±0.10	42	0.58
Combination of drug A and drug B-3	1.28±0.25	63	0.37

Note 1) product of relative indices of the individual administration groups: 0.86 × 0.58 equals 0.50.

Note 2) both hind limb edema volumes are expressed as mean ± standard error of 6 mice per group.

The drug A and the drug B-3 were combined, the Edema Index was greatly reduced, and the product of the relative indexes of the Edema Index was smaller than that of the drug A and the drug B-3, respectively. On the other hand, neither the drug A3 mg/kg-alone group nor the drug B0.2mg/kg-alone group exhibited a strong Edema-suppressing effect, and the Edema Index was not reduced to 50% or less of that of the control group.

TABLE 4

Is tested for medicament	Edema Index	Reduction ratio (%)	Relative index
				Control group	4.20±0.09
Drug A10mg/kg single administration group	2.93±0.22	19	0.81
				Agent B-41mg/kg single administration group	3.41±0.16	30	0.70
Combination of drug A and drug B-4	1.11±0.23	74	0.26

Note 1) product of relative indices of the individual administration groups: 0.81 × 0.70 ═ 0.57.

Note 2) the volume of edema in both hind limbs is expressed as the mean. + -. standard error of 8 mice in each group.

The drug a and the drug B-4 combined group significantly decreased Edema Index, and when F detection of interaction was performed by a statistical technique (two-way analysis of variance) for directly evaluating the synergistic effect, significant synergistic effect (interaction) (p 0.0083) was confirmed, and a significant synergistic effect was confirmed by combined administration. On the other hand, neither the group administered with the drug a alone nor the group administered with the drug B alone exhibited a strong Edema-suppressing effect, and the Edema Index was not reduced to 50% or less of that of the control group.

Example 2

The same conditions as in example 1 were used except that the amounts of the agent A and the agent B-4 were changed from 1mg/kg to 3mg/kg or 10mg/kg and 6 mice were used, and the results of the Edema Index measurement are shown in Table 5 and FIG. 5.

TABLE 5

The tested medicament	Edema Index	Reduction ratio (%)	Relative index
				Control group	4.04±0.16
Drug A3mg/kg single administration group	4.18±0.29	-3	1.03
				Drug B-43mg/kg single administration group	2.46±0.22	39	0.61
Combination of drug A and drug B-4(3mg/kg)	1.21±0.29	70	0.30
				Drug B-410mg/kg single administration group	1.86±0.19	54	0.46
Combination of drug A and drug B-4(10mg/kg)	0.76±0.37	81	0.19

Note 1) product of relative indices of the individual administration groups (agent A and agent B-43 mg/kg): 1.03 × 0.61 ═ 0.63.

Note 2) product of relative indices of individual administration groups (agent a and agent B-410 mg/kg): 1.03 × 0.46-0.47.

Note 3) both hind limb edema volumes are expressed as mean ± standard error of 6 mice per group.

The Edema Index was greatly reduced in the group administered with the combination of the drug a and the drug B-4, and significant synergistic effect (interaction) was confirmed by F detection by two-way anova (p: 0.0243), and significant synergistic effect was confirmed by the combined administration. On the other hand, in the single administration groups in which the dose of the agent B-4 was increased by 3mg/kg and 10mg/kg, respectively, the EdemaIndex was reduced only to 39% and 54% of those in the control group, respectively.

Claims (15)

1. A preventive and/or therapeutic agent for articular rheumatism, characterized by comprising 2-benzyl-5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -2H-pyridazin-3-one and COX2 inhibitor.

2. The preventive and/or therapeutic agent for an articular rheumatism according to claim 1, characterized in that the COX2 inhibitor is a COX2 inhibitor of a carboxylic acid system, an enolic acid system, or a tricyclic system.

3. A preventive and/or therapeutic agent for articular rheumatism according to claim 1, characterized in that the COX2 inhibitor is an inhibitor selected from the group consisting of diclofenac or a salt thereof, ketoprofen or a salt thereof, meloxicam and celecoxib.

4. The preventive and/or therapeutic agent for an articular rheumatism according to claim 1, characterized in that the articular rheumatism is accompanied by joint inflammation.

5. The preventive and/or therapeutic agent for articular rheumatism according to claim 1, characterized in that the formulation is an oral preparation.

6. A method of treating articular rheumatism characterized in that effective amounts of 2-benzyl-5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -2H-pyridazin-3-one and a COX2 inhibitor are administered.

7. The method of treatment of claim 6, wherein the COX2 inhibitor is a carboxylic acid, enolic acid, tricyclic COX2 inhibitor.

8. A method of disposal according to claim 6, wherein the COX2 inhibitor is an inhibitor selected from the group consisting of diclofenac or a salt thereof, ketoprofen or a salt thereof, meloxicam and celecoxib.

9. A procedure as claimed in claim 6 wherein the articular rheumatism is accompanied by joint inflammation.

10. A method of treatment as claimed in claim 6, wherein the method of administration is oral.

Use of 2-benzyl-5- (4-chlorophenyl) -6- [4- (methylthio) phenyl ] -2H-pyridazin-3-one and COX2 inhibitor for the manufacture of a preventive and/or therapeutic agent for articular rheumatism.

12. The use according to claim 11, wherein the COX2 inhibitor is a carboxylic acid, enolic acid, tricyclic COX2 inhibitor.

13. The use of claim 11, wherein the COX2 inhibitor is an inhibitor selected from the group consisting of diclofenac or a salt thereof, ketoprofen or a salt thereof, meloxicam, and celecoxib.

14. Use according to claim 11, wherein the articular rheumatism is accompanied by joint inflammation.

15. The use of claim 11, wherein the dosage form is an oral formulation.