WO1993019066A1 - Imidazopyridine derivative and medicine - Google Patents

Abstract

An imidazo[1,2-a]pyridine derivative represented by general formula (I) and a pharmacologically acceptable salt thereof, wherein R1 represents hydrogen or alkyl; R?2 and R3¿ may be the same or different from each other and each represents alkyl, hydroxy, alkoxy or halogen; and X represents hydrogen, halogen or alkoxy. This compound not only is useful for controlling inflammation but also has the effect of controlling the destruction of joints, which existing antiinflammatory agents do not have, thus being efficacious in treating rheumatoid arthritis.

Description

 Incense

 Imidazopyridin derivatives and concealed products

 The present invention relates to an imidazo [1,2-a] viridine derivative represented by the following general formula [I] and a pharmacologically acceptable salt thereof.

式中、 R ¹は水素又は了ルキルを表し、 R^a、 R^aは同一又は異なって 氷素、 アルキル、 ヒ ド σキシ、 アルコキシ又はハ Dゲンを表す。 X は水素、 ノ、ロゲン又はアルコキシを表す。 [I]

In the formula, R ¹ represents hydrogen or alkyl; R ^a and R ^a are the same or different and represent chromium, alkyl, hydroxy, alkoxy, or halogen. X represents hydrogen, hydrogen, logene or alkoxy.

More specifically, the present invention relates to a compound in the above formula [I], wherein RR \ R ³ is hydrogen and X is hagen, in particular, odo.

 The compound of the present invention is useful for rheumatoid arthritis.

 Background technology

 Rheumatoid arthritis is an autoimmune disease that begins with pain in the peripheral small joints of the extremities and spreads to large joints in the trunk, inflammation of joint slips and destruction of joint tissues. .

Various studies have been conducted on the causes of the above-mentioned symptoms of rheumatoid arthritis. Search for stronger anti-inflammatory agents based on the mechanism of action of applying anti-inflammatory agents to rheumatoid arthritis Is progressing. Prostaglandin (PG), which is produced from arachidonic acid by cyclooxygenase, is regarded as a mediator of inflammation and plays an important role in inflammation.

 了 Rubilin indomethacin, which is widely used as a stabilizing anti-inflammatory pain agent, inhibits cyclooxygenase, and therefore biosynthesis of brostaglandin (PG), toxinboxane (TX), etc. By reducing the amount, anti-inflammatory and spear pain effects can be obtained.

Various leukotrienes (LTs) produced from arachidonic acid by lipoxygenase have been emphasized in relation to bronchial asthma rather than inflammation. However, LTB ₄ has potent polymorph垓球leukocyte migration action, since such that there is the effect of increasing the active oxygen production, the importance of re Pokishigena peptidase g path is noted in inflammatory reactions.

 There are several known drugs that inhibit lipoxygenase activity and suppress the production of LT and lipoxin (LX), but none of them are clinically used yet in the basic experimental stage, but there is no JD.

 Drugs that inhibit both cyclooxygenase and lipoxygenase, called dual insulin inhibitors, are being sought to be used as more potent anti-inflammatory thorns in the treatment of rheumatoid arthritis. ing.

 In addition to the above, various compounds that have an anti-inflammatory effect and are effective for arthritis have been reported.

It has been found that compounds having a 2,6-di-tert-butylphenol group have excellent anti-inflammatory effects (Japanese Patent Application Laid-Open No. 57-21375, Japanese Patent Application Laid-Open No. 57-150692). No.). ά

 In addition, 2- (3,5-di-tert-butyl-4-hydroxylunil) imidazo [1,2-a] pyridine has a potent inhibitory effect on rageragenin edema and adjuvant arthritis. (Chem. Pharro. Bull. 31, 3168 (1983)).

 Further, <0/89/03833 International Publication discloses that a compound having the same basic skeleton as the compound of the present invention described later has a bone resorption inhibiting action and is effective for osteoporosis. No disclosure is made, and there is no mention of a therapeutic effect on rheumatoid arthritis based on the specific effects of the compound of the present invention (to be described later, “double effect (doubling effect)”). JP-A 61-152681 describes that a compound similar to the compound of the present invention has antithrombotic and cardiotonic effects. However, the compound of the present invention has a therapeutic effect on rheumatoid arthritis based on a dual effect. There is no mention of.

 The main effects of currently used anti-inflammatory analgesics have been attributed to cyclooxygenase inhibitory activity. These drugs ¾ inhibit lipoxygenase, inhibit IL-1 migration, -It does not have the purpose of production of ushi-bushi deterrent according to 1.

 Apart from the above, in the treatment of rheumatoid arthritis, non-steroid anti-inflammatory drugs, immunomodulators, anti-inflammatory drugs, immunosuppressants, steroids, etc. are used according to the symptoms.

 These drugs improve inflammation and pain, but do not stop the progress of joint destruction. It is known that the use of steroids may cause serious side effects such as exacerbation of osteoporosis-like symptoms.

Considering the above-mentioned shortcomings of existing drugs, the mechanism of rheumatoid arthritis While examining nysm, at the site of inflammation, activated leukocytes (Mak π phage) play cytokins such as interleukin-1 (IL-1), and in particular, It was found that it causes membrane proliferation, cartilage destruction, and osteotomy, causing joint anaphylaxis, and this has attracted attention as an important factor in joint anatomy.

 Therefore, by applying a drug that has an anti-inflammatory effect as well as an anti-node destruction effect to rheumatoid arthritis, it is possible to suppress inflammation and pain as well as the symptomatic treatment of rheumatoid arthritis, Has been found to be particularly effective in treating rheumatoid arthritis.

 Disclosure of the invention

 In view of the above, the present inventors have found that they have an effect of suppressing inflammation and having an excellent inhibitory effect on joint destruction, and exhibiting a synergistic effect due to the simultaneous occurrence of these two actions. Research was conducted to obtain a new type of chronic orchid rheumatoid arthritis drug. The present inventors have referred to this synergistic effect as “double effect” and have devoted themselves to the discovery of a drug having this double effect.

Japanese Patent Application Laid-Open No. 3-77894 describes that a methylene diphosphonic acid compound has both an anti-inflammatory action and an inhibitory action on bone bone and is effective for arthritis and the like. Although the double effect cannot be said to have been originally proposed by the present inventors, the effect disclosed here is not strong enough to be put to practical use, and a synergistic effect caused by the simultaneous occurrence of the two effects. No double effect according to the present invention is intended for the first time by the present invention, since no specific effect is mentioned. O

 The present inventors have found that the compound represented by the general formula [I] is suitable for the above purpose, and have completed the present invention.

 The gist of the present invention lies in the structure itself of the compound represented by the general formula [I].

In the general formula [I], the alkyl represented by R ³ or ³ is preferably a straight-chain or branched K-type alkyl group having 1 to 4 amino acids, such as methyl and ethyl. , N-propyl, isoprovir, π-butyl, sec-butyl, tert-butyl and the like.

The alkoxy represented by R ^3, R ^a, lay preferred linear or branched techniques like low扱了alkoxy carbon number 1-4, for example, main butoxy, E butoxy, n- propoxy, i Sopu Poxy, n-butoxy, isobutoxy, sec-butoxy and the like can be mentioned.

Examples of the halogen represented by R ² and R ³ include chlorine, bromine, fluorine, iodine and the like.

 Examples of the halogen represented by "include chlorine, bromine, fluorine, iodine, and the like.

 The alkoxy represented by X is preferably a straight-chain or branched low-working alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy, π-butyl α-poxy, isopropoxy, η- Butoxy, isobutoxy, sec-butoxy and the like.

The structural features of the compound of the present invention are: (1) having imidazo [l, 2-a] pyridine skeleton; and (2) the imidazo [1, 2-a] pyridine skeleton has a tert- S-substituted with butyl-4-hydr σ-xyphenyl group, (3) The above 3-tert-butyl-4-hydr π-xyphenyl group is either anonymous or substituted with halogen or alkoxy.

 Furthermore, in addition to the above, the structural features of the present invention include, in addition to the above ①, ②, and ③, the imidazo [1,2-a] pyridine skeleton of ② above has a g 换 group in addition to ① There is no thing.

 More specifically, a structural feature of the compound of the present invention is that, in the above ③, the 5-position of the 3-tert-butyl-4-hydroxyphenyl group is substituted by a halogen, particularly a halide.

 The compound of the present invention having the above structural characteristics is a novel compound not described in the literature, exhibits excellent pharmacological action as described below, and has low toxicity.

The aforementioned 2- (3,5-di-tert-butyl-4-hydroxyhydroxynyl) imidazo [1,2-a] pyridine has an inhibitory effect on power-lagenin edema and an effect on adjuvant arthritis. However, as described in detail below, it does not have an IL-1 release inhibitory action, and thus cannot attain the pharmacological action by the double effect aimed at by the present invention. Further, as will be described in detail later, the gastric mucosa has a very strong harmful effect, so that it cannot be put to practical use. Considering the correlation between the double effect of the compound of the present invention and the structural characteristic of the compound of the present invention, imidazo [1,2-a] bili The phenyl substituted at the 2-position of the gin skeleton has hydroxy as a 4-position substituent, a tert-butyl group as a 3-position substituent, and a penta- or 5-position substituent. Is thought to be due to having an alkoxy or not having a g-substituent at the 5-position. The double effect of the compound of the present invention is that the compound of the present invention has a chemical structure in which the halogen substituted as the 5-position substituent of phenyl substituted to the 2-position of the above imidazo [1,2-a] viridine skeleton. In particular, the manifestation of having an evil is not continuous.

 The compound of the present invention can be produced, for example, by the following method:

(Wherein RR ³ , R ³ and X are the same as above, and Z represents a halogen.) Compound [II] and the 2-aminopyridine derivative are reacted in a solvent inert to the reaction in the presence of a base or [I] can be produced by reacting in the absence of 0 to 150, preferably 0 to 100. Examples of the reaction solvent include alcohols such as methanol, ethanol, and isopropyl alcohol; hydrated carbons such as benzene and toluene; dioxane; ethers such as 1,2-dimethoxyethane; Acetonitrile, Ν, Ν-dimethylformamide and the like can be used. Above all, low-handling alcohol is preferred. Examples of the base include inorganic salts such as alkaline hydrogen carbonate (eg, sodium hydrogen carbonate) and carbonates (eg, potassium carbonate). An organic base such as a group or triethylamine can be used. When reacting

H varies depending on the raw materials, the type of solvent and the type of base used, but usually 1 to 24 hours is appropriate. It is preferable that the amount of the 2-minobilizins used is at least equimolar to [II]. In addition, the reaction may be carried out using surplus 2-amino minopyridines instead of the above bases. In this case, it is generally preferable to use 2-amino viridines in an amount of 2 mol / l to 1 mol of [II].

 The starting material [II] will be described as a reference example, but can be produced as follows.

(Wherein, R ¹ is the same as above. X ′ represents H, Br, CI or I)

When X is H, Br, CI or I

In the presence of 1- to 5-fold amount of a silylating agent (for example, anhydrous acetic acid, acetyl chloride) and a suitable base (for example, viridine), 1- to 50-fold amount of 2-tert-butylphenol is used. In solvents or inert solvents (eg benzene, toluene Hydrocarbons such as ethylene, ethers, ethers such as tetrahydrofuran, dioxane, halogen solvents such as π-form, methylene chloride, or N-dimethylformamide). Reaction yields 2-acetyloxy-tert-butylbenzene. This is dissolved in an inert solvent such as nitromethane, carbon disulfide, nitrobenzene, and chlorobenzene in a Lewis acid (for example, stannic chloride, titanium tetrachloride, aluminum chloride, aluminum trichloride, boron trifluoride ethereal). 2-tert-butyl-4-acylphenol can be obtained by reacting with 0-30 t. This compound is prepared by combining 2-tert-butylphenol and a acylating agent (eg, acetylk D-lide) in an inert solvent, preferably 1,2-dichloromethane, in the presence of lewis acid. It can also be obtained by reacting at 0 to 30 t. 2-tert-butyl-4-acylphenol is added in an inert solvent such as bromine in a mixture of acid and water when the product is X = Br and in an inert solvent such as chloroform when the product is X = C1. If the product is tert-butyl chlorite and the product is [] (= 1 react with iodine monochloride in a mixture of stearic acid and water, or hydrated alcohol (preferably hydrated ethanol, hydrated methanol) Or iodine or iodic acid in a mixed solvent of ethyl acetate, suisui isopropyl alcohol), hydrated cetonitrile, or acetic ester (preferably ethyl citrate). By reacting, it is possible to obtain 2-tert-butyl-4-yl-6-halogenophenols in which various halogens have been introduced into the position adjacent to the hydroxyl group. 0 in mouth form, ether, diacid, ethyl ethyl ester, etc. When reacted with a halogenating agent, preferably a brominating agent, more preferably bromine at ~ 30 t, the general formula

The compound represented by [II] can be obtained. In the case where X is fluorine or alkoxy, it can be manufactured as in the reference example described later.

 The present compound can be synthesized in addition to the above, for example, as follows. .

 (1) A method using the following route by passing ammonia gas under inert conditions in an inert solvent such as DMP.

[I]

(2) A method involving the following route by heating and reacting with hydrogenated benzoic acid such as bromopernic acid at 50 to 150 t.

 c n

このようにして製造される目的化合物 [ I ] 及び製造中間体は、 それ自体公知の手段により、 遊雜塩基の形、 又は酸付加塩の形で、 例えば、 濃縮、 液性変換、 転溶、 溶媒抽出、 結晶化、 再結晶、 分溜， クロマ トグラフィ 一等により単雜精製することができる。 (3) A method of reacting with a hydrogen halide such as hydrogen chloride in an inert solvent such as n-benzene at 50 to 150, via the route below.

The target compound [I] and the intermediate produced in this manner can be produced in a form of a free base or an acid addition salt by means known per se, for example, concentration, liquid conversion, phase transfer, It can be purified simply by solvent extraction, crystallization, recrystallization, fractionation, chromatography, etc.

 Among the compounds of the present invention, examples of the ΨI acid • 1 addition salt of the compound represented by the general formula [I] include salts of base acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; Salts of organic acids such as carboxylic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid and the like can be mentioned.

 When the compound of the present invention is administered as a medicament, the compound of the present invention may be used as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example,

It is administered to animals including humans as a pharmaceutical composition containing 0.1% to 99.5, preferably 0.5X to 9DX.

As the carrier, one or more solid, semi-solid, or liquid diluents, fillers, and other formulation aids are used. The pharmaceutical composition is administered It is desirable to administer in units. The pharmaceutical composition of the present invention can be administered intravenously, orally, intraosseously, topically (eg, *, ophthalmic) or rectally. Needless to say, it is administered in a type III suitable for these administration methods. Perot administration is particularly preferred.

 It is desirable to set the dose as a therapeutic agent for rheumatoid arthritis in consideration of the patient's condition such as age and weight, the administration route, the sex and extent of the disease, etc. In the case of oral administration per day, the amount of the active ingredient of the present invention is generally in the range of 1 (! To 1500 ing / hit, preferably in the range of 50 to 600 rag / hit. The following are sufficient, and conversely, may require higher doses, and may be given in 2 to 4 divided doses per day.

 Perforation is performed in solid or liquid dosage units such as powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, tablets, sublingual tablets, etc. Can be carried out depending on the dosage form.

 Powders are prepared by comminuting the active substance to an appropriate degree. Powders are prepared by comminuting the active substance with an appropriate degree of fineness and then with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate such as starch, mannitol. Flavoring agents, preservatives, dispersing agents, coloring agents, fragrances and other substances may be mixed as necessary.

Forcepsel II is prepared by first converting powdered powders, powders, or granules as described in the section on tablets into a forcepsell shell such as a gelatin capsule. It is manufactured by filling. Lubricants and glidants, such as colloidal silica, talc, magnesium stearate, calcium stearate, solid poly 00309

 13

It is also possible to mix a substance such as tylene glycol into a powder state and then perform the filling operation. Disintegrators and solubilizers, for example, carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropyl mouth cellulose, croscarmester sodium, carboxystarch sodium, calcium carbonate, sodium carbonate The addition of lithium and can improve the efficacy of the drug when the capsule is taken.

In addition, the powder of this product can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant, and wrapped in a gelatin sheet to prepare a soft capsule. Tablets are made by preparing a powder mixture, granulating or slugging, then adding a disintegrant or lubricant and pressing. The powder mixture is obtained by mixing an appropriately powdered substance with the above-mentioned diluent or paste and, if necessary, a binder (eg, carboxymethylcellulose sodium, hydroxybile, virucellulose, methylcellulose, hydroxyb). Mouth virmethylcellulose, gelatin, polyvinylidene, polyvinyl alcohol, etc.), dissolving and propellant (eg, paraffin, wax, hydrogenated castor oil, etc.), resorbent (eg, tetrasalt) ) And adsorbents (eg, pentonite, kaolin, dicalcium phosphate, etc.). The powder mixture can be moistened with a binder, for example, syrup, powdered glue, gum arabic, cellulose solution or polymer solution, and then forced through a sieve to form granules. Instead of granulating the powder in this way, it is also possible to first apply a tableting machine and then break the obtained incomplete slag into granules. By adding lubricating agents such as stearic acid, stearate, talc, mineral oil, etc., the granules thus produced can be prevented from sticking to each other. . The lubricated mixture is then struck.

 The material thus manufactured can be coated with a film coating or sugar coating.

 Alternatively, the drug may be directly compressed into tablets after mixing with a flowable inert carrier without going through the steps of granulation and slag formation as described above. A transparent or translucent protective coating consisting of a hermetically sealed shinac coating, a coating of sugar molecular material, and a top coating consisting of wax can also be used.

 Other oral dosage forms, such as solutions, syrups and elixirs, can also be formulated in dosage unit form so that a given quantity contains a certain amount of drug. Syrup is produced by dissolving the compound in an appropriate aqueous flavor solution, and elixir is produced by using a non-toxic alcoholic carrier. The agent is formulated by dispersing the compound in a toxic carrier. Solubilizers and emulsifiers (eg, ethoxylated isosteryl alcohols, polyoxyethylene sorbitol esters), preservatives, flavor enhancers (eg, palmit oil, saccharin), etc. Can also be added as needed.

 If necessary, the dosage unit formulation for microdose administration can be microbubulated. The tatami formula can also provide a prolonged duration of action or sustained release by coating or embedding in polymers, waxes, etc.

Intra-therapeutic administration is for subcutaneous, intramuscular or intravenous injection. It can be done in dosage unit form, for example, in the form of solutions or SIS agents. These are accomplished by suspending or dissolving a fixed amount of the compound in a non-toxic liquid carrier suitable for the purpose of injection, such as a permanent or oily medium, and then sterilizing the suspension or solution. Manufactured. Alternatively, an aliquot of the compound may be placed in a vial, and the vial and its contents sterilized and sealed thereafter. Spare vials or carriers may be provided with the powdered or * dried active ingredient for dissolving or mixing immediately prior to administration. Non-toxic salts or salt solutions may be added to make the injection solution isotonic. Further, stabilizers, preservatives and emulsifiers can be used in combination.

 Rectal administration involves mixing the compound with a low-touch-point water-soluble or insoluble facet, such as polyethylene glycol, cocoa butter, esters (eg, myristyl palmitate), and mixtures thereof. This can be done by using suppositories.

Among the above-mentioned compounds of the present invention, in the general formula [I], the compounds in which R ′, R ^a , and R ⁸ are eternal and X is odo are newly selected as the compounds of the present invention ( select). This was obtained according to Example 2 below.

 The compound of Example 2 had a much better pharmacological effect than the other compounds represented by the general formula [I]. When examining the double effect, the other compound had an inferior effect as compared with the compound of Example 2. The present invention relating to the compound of Example 2 has been completed only by encountering this fact.

Accordingly, the present invention provides a compound represented by the general formula [I]: RR ² , R ^a is Korimoto, and, X is established only compounds which are Yodo.

 The invention's effect

 Since the compound of the present invention has both an anti-inflammatory effect and an inhibitory effect on joint destruction (an inhibitory effect on bone resorption and an inhibitory effect on plasma membrane proliferation) and low toxicity, it is useful for chronic joint I) It can be used for the improvement of inflammatory symptoms such as osteoarthritis, osteoarthritis, pain pain, juvenile inflammation, cervical dystrophy, and pain. In addition, it has an antiallergic effect, so it can be used to improve allergic symptoms such as bronchial asthma, chronic mushroom measles, allergic * flame, and Toby dermatitis. It is a safe drug because it has few side effects such as gastrointestinal disorders and low toxicity.

 BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in further detail with reference to Reference Examples, Examples, Test Examples, and Formulation Examples of the compound of the present invention.

Reference example 1

 Manufacture of 2,3'-dibutene-5'-tert-butyl-4'-hydroxy

 (First step) Mix 15 g of 2-tert-butylphenol, 15 ml of pyridine, and 12 g of ice-free ^ acid, and heat on an ice bath for 2 hours. After the reaction, allow to cool, add water, and stir for 1 hour. The mixture was extracted with n-hexane, and the n-hexane layer was washed with water, dilute hydrochloric acid, water, dilute sodium carbonate solution, and water, and dried with magnesium sulfate. The solvent was distilled off to obtain 19.2 g of 2-tert-butyl phenyl acetate as a colorless oil.

(2nd step) 18 g of 2-tert-butylphenyl acetate was added to Dissolve in 70 ml of tan and add dropwise 27 g of titanium tetrasupported at room temperature with stirring. After stirring at room temperature for one day, the reaction mixture is poured into ice containing 50 ml of concentrated humic acid, and the precipitate is extracted with ether. Wash the ether calendar with water and dry with magnesium sulfate. The solvent is distilled off, n-hexane is added to the residue, and the precipitate is removed. Recrystallization from a mixture of ethanol and Eihan gave 11.3 g of 3'-tert-butyl-4'-hydroxyacetotofunonone as pale brown needles.

 (Alternative method of the second step) This compound can also be produced as follows.

 137.5 g of cetyl kanji was dissolved in 1,000 ml of 1,2-dichloroethane, 456 g of stannic chloride was added under ice-cooling and stirring, and the mixture was stirred at the same temperature for 10 minutes. At the same temperature, 250 g of 2-tert-butylphenol was added dropwise over about 1 hour, and the temperature was returned to room temperature, followed by stirring for 3 hours. The reaction was poured into ice and extracted with about 3 liters of ether. The ether calendar was washed three times with water, further washed with saturated saline ice, and then dried and smoked with magnesium sulfate. After concentrating until the total volume was 700-800 ral, approximately the same amount of n-hexane was added, and the precipitate was removed by tt, washed with n-hexane, and dried. 168.5 g of a white powder was obtained. In the same manner, from the mother liquor, another 6.7 g of crystals were obtained by making bran. Break point 167 ~: 168168

 (Third step) In a solution of 3'-tert-butyl-4'-hydroxyacetofunnon 6. suspended in a mixture of 60 ml of acetic acid and water UOrol, 5.4 g of bromine and 30 ml of 80X diacid are stirred at room temperature under stirring. And dripped. The reaction mixture is further

After stirring for 2 hours, water was added, the precipitate was collected, washed with water, and 3′-bromo-4′-hydroxy-5′-tert-butylacetotof; 8.56 g of t-non was converted into white crystals. ^ / ¹ L 0 (Step 4) Dissolve 8.56fif of 3'-bromo-4'-hydroxy-5, -tert-butylacetatephenone in 150 ral of polyester and, at room temperature with stirring, convert 5.1 g of bromine to 50 nl of ether. Dissolve and drip. The reaction mixture is stirred at room temperature for another hour. The ether shield was removed, washed with water, sodium hydrogen sulfite, and water, and dried over magnesium sulfate. The solvent was distilled off to obtain 11.2 g of 2,3′-dibuπ-mo-5′-tert-butyl-4′-hydroxyacetophenone as a pale brown oil.

 In a similar manner, 4'-hydroxy-5'-tert-butyl-iso-phenphenone is brominated to give 2-bromo-4'-hydroxy-5'-tert-butyl-isopropyl phenonone. Was.

Reference example 2

 3, -tert-butyl -4'-hydroxy-5'-k π π acetophenone

 3. Suspension of 60 g of 3, -tert-butylile-4'-hydroxyacetophenone in 500 nl of a mouth form, and lowering 34.9 g of tert-butyl hypochlorite at room temperature. The reaction mixture is further stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from a mixture of ethanol and ice. 3'-tert-butyl-4, -hydroxy-5'-chlorothiophene: 66 g of c-non white Obtained as crystals.

 This was brominated according to the method of the fourth step in Reference Example 1 to obtain 2-bromo-3'-tert-butyl-4, -hydroxy αxy-5, -chlorobutane. . Reference example 3

 Production of 2-bromo-3'-tert-butyl-4, -hydroxy-5'-iodoacetpheno

(Step 1) Method a: 3'-tert-butyl-4'-hydroxyxacetopheno 丄

Heat 40 g of acetic acid in 550 ml of acetic acid to dissolve, add 275 g of water at a time with stirring, stir, and allow to cool to room temperature. 35.5 g of iodine monochloride is dissolved in 70 nU of acetic acid and added dropwise over 2 to 2.5 hours. Stir at room temperature for 1 hour. Add water to the reaction mixture and extract with ether. The ether layer is washed with condyles of water, a saturated aqueous solution of sodium bicarbonate and saturated saline, and dried with magnesium sulfate. The solvent was distilled off, and the residue was crystallized from a mixed solvent of ethanol and ice to give 30.8 g of 3'-tert-butyl-4-hydroxy-5-cetonitrile as white crystals. Was.

Method b: 34.5 g of 3'-tert-butyl-4'-hydroxy-terminated pentanone is dissolved in 520 ml of ethanol, and 22.76 g of iodine is added. Then dissolve 3g of iodic acid in 170ml of water and add 60 ~? For 3 hours and released overnight. Ethanol was distilled off, and the residue was dissolved in ft-ethyl acetate. The ethyl acetate solution was washed with water, washed with sodium thiosulfate ice solution, washed again for a long time, and dried with magnesium sulfate. The solvent was distilled off, and n-hexane was added to the residue for crystallization to obtain 46.9 g of 3′-tert-butyl-4′-hydroxy-5′-hodoacetopentanone. Melting point 100-102 t

 (Second step) Method a: Dissolve 50 g of 3'-tert-butyl-4'-hydr sigma-xy-5'-hodoacetophenone in 1000 ml of ether, and add 28.8 g of bromine to 1.5 ml under ice-cooling and stirring. Add dropwise over 2 hours, and stir at room temperature for 30 minutes. Water is added to the reaction mixture, and the ether layer is separated, washed with water, washed with saturated saline ice, and dried over magnesium sulfate. The solvent was distilled off to obtain 66 g of 2-bromo-3'-tert-butyl-4'-hydroxy-5'-iodine-setofonone as a pale yellow oil.

Method b: 3'-tert-butyl-4'-hydroxy-5, -method To a mixture of 21.96 g, 20% of an il% hydrogen fluoride-extended ice solution and 300 ml of clog mouth form was added dropwise with lg of bromine at an external temperature of 20 over 45 minutes, followed by drying at the same temperature for 1.5 hours. The reaction solution was washed with water, washed with an aqueous solution of sodium thiosulfate, washed again with water, and baked with magnesium triluate. The solvent was distilled off to obtain 29.6 g of 2-promote-3'-tert-butyl-4'-hydroxy-5, -thiophene.

 NMR (CDC) δ: 1.4K9H, s), 4.36 (2Η, s), 6.06 (1H, s),

 7.94 (1H, d, J = 2Hz), 8.20 (1H, d, J = 2Hz)

Reference example 4

 Preparation of 3 * -tBrt-butyl-4'-hydroxy-5'-fluoro pi-acetophenone (1st step) 3'-tert-butyl-4, -hydroxyacetophenone 13.lg溶解 Dissolve in 150 ml of acid, dissolve 7.5 g of 60 nitric acid in 10 ml of acetic acid, and take a short time at 25 tons. The reaction solution is poured into ice and the precipitate is extracted with n-hexane. Wash the extract with water and dry over magnesium sulfate. The solvent was concentrated, and the residue was crystallized from a mixture of methanol and water to give 13.5 g of 3-tert-butyl-4'-hydroxy-5'-nitrophenophenone. Obtained as crystals.

(Second step) 3'-tert-butyl-4, -hydroxy-5'-ditoro 17.4 g of cetofenonone, 21 g of anhydrous carbon dioxide, and 21 g of methyl iodide were added to H, N- Mix with 180πι1 of dimethylform, and stir at room temperature for 40 hours. Add water to the reaction solution and extract with a mixed solvent (ether: π-hexane = 1: 1). The extract is washed with ice and dried over magnesium sulfate. The solvent was distilled off to obtain 17.5 g of 3'-tert-butyl-4'-methoxy-5'-nitroacetophenone as a pale yellow oil. (Third step) 17.5 g of 3'-tert-butyl-methoxy-5'-ditroacetophenone is dissolved in 87.5 ml of ethanol, and 35 ml of concentrated acid is added. 57 g of stannous chloride (dihydrate) is dissolved in 70 nl of concentrated acid, and the mixture is stirred at room temperature for 2 hours. The reaction mixture was added to a 20X sodium hydroxide solution (500ral) under cooling and stirring, and the precipitate was extracted with ether.The ether brow was washed with water, then with saturated saline, and dried with magnesium sulfate. The solvent is distilled off. The residue was crystallized from ethanol and ice to give 13.95 g of 3'-tert-butyl-4, -methoxy-5'-methylaminotetrafluorophenone as white crystals.

(Fourth step) 3, -tert-Butyl-4'-Methoxy-5 ·-Rino-mino R-sethfnon l. Og is dissolved in 1.2 ml of concentrated conc. Acid and water {π}, followed by- Cool to 5 t, dissolve 0.35 g of sodium nitrite in 1 ml of ice, and add dropwise at the same temperature.

After stirring for 10 minutes, add 60 hexafluorophosphoric acid 1.2ral at a time and stir at -5 t for another 10 minutes. The precipitate is collected, washed with ice, then washed with a mixed solvent of ethanol and ether, and dried to give 2-methoxy-3-tert-butyl-5-cetylbenzenediazoni. Aluminum hexafluorophosphate was obtained as a white powder. Melting point 110-113

(Fifth step) 1. 46 g of 2-methoxy-3-tert-butyl-5-butylcetylbenzenediazoniumhexafluoate is added to 20 ml of toluene in 3BS, and the mixture is heated under reflux for 40 minutes. After cooling, aqueous sodium hydrogen carbonate solution is added, and the precipitate is extracted with ethyl acetate. After drying the alcohol with magnesium sulfate, the solvent was distilled off. The residue was applied to U-gel gel chromatography and eluted with a mixed solvent (ethyl acetate: n-hexane = 1: 8) to give 3'-tert-butyl-4'-methoxy-5 ' 0.34 g of -fluoro α-setofonone was obtained as a pale yellow oil. (Sixth step) A mixture of 3,5 g of 3'-tert-butyl-4'-methoxy-5'-fluoroethylene and 13.5 g of pyridin clay is stirred at 220 for 40 minutes. After cooling, the mixture was added to a mixture, extracted with ethyl acetate, ethyl acetate S was washed with water, and dried with magnesium sulfate. The solvent was distilled off, the residue was applied to a silica gel column, and eluted with a mixed solvent (ethyl acetate: π-hexane = 1:10) to elute 3'-tert-butyl-4'-hide sigma -5, -Fluorothiophenone 1. lg was obtained as white crystals.

 This was converted to butyl in the same manner as in Reference Example 3 to obtain 2-bromo-3'-tert-butyl-5'-fluoro-4, -hid α-hydroxysetphenone.

Reference example 5

 Production of 3'-tert-butyl-4'-hydroxy-5'-methoxyacetphenone (1st step) 3, -tert-butyl-4'-hydroxy-5'-method Suspend 12.6 g and 6.3 g of copper sulfate pentahydrate in 350 ml of 10X sodium hydroxide solution, and heat and reflux for 1 hour and 30 minutes. When heated, the insolubles were passed through, the liquid was acidified with hydrochloric acid, and the precipitated crystals were collected. The target compound was obtained as gray crystals by recrystallization from black hole form.

(Second step) Suspension of 0.79 g of 60X hydrated sodium in 30ral of Ν, Ν-dimethylformamide and 3'-61 "1: -butyl-4 ', After addition of 2.0 g of 5'-dihydroxy-terminated funfunnon, the mixture was stirred at room temperature for 30 minutes, and then cooled again with ice, and 1.43 g of methyl iodide was added dropwise. After stirring for a period of time, the mixture was poured into ice and ice, and the mixture was acidified with hydrochloric acid, and the precipitate was extracted with ether, subjected to ether chromatography, applied to silica gel column chromatography, and the solvent (chloroform form: hexane) was added. = 1: 1) to give 1.9 g of the desired compound as a pale yellow oil. This compound was brominated in the same manner as in Conventional Example 3 to obtain 2-bromo-3′-tert-butyl-4′-hydroxy-5′-methoxyacetphenone. Example 1

 Production of 2-C3-pum-5-tert-butyl-4 -hydroxyphenyl] imidazo [1,2-a] viridine

 2,3′-dibu α-5′-tert-butyl obtained in the same manner as in Reference Example 1.

Dissolve 11.2 g of hydroxyacetofunnon in 100'rol of ethanol. 2-O-Minoviridine 12. Og was added, and the mixture was carried at room temperature for 30 minutes, and then heated and refluxed for 1 hour and 30 minutes. After shrinking to about half the volume, add water and extract the precipitate with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and the solvent is distilled off. Add ethanol to the residue and remove the precipitated crystals. The mother liquor is subjected to silica gel gel chromatography and eluted with a developing solvent (chloro η form: methanol = 60->>) to obtain more crystals. These are combined and a mixed solution of ethanol and isopropyl ether is obtained. Recrystallization from a solvent gave 7.3 g of the desired compound as pale yellow crystals.

 185 to 186

 Elemental analysis (as C ^ H ^ BrNaO)

 Theory% (%) C: 53.11 H .96 N: 8.11

 Measured child (%) C: 53.03 H: 4.89 N: 8.10

Example 2

 2- (3-tert-butyl-4-hydroxy-5-hydroxyphenyl) imidazo

 [1.2-a] Production of viridin

49.4 g of 2-bromo-3, -tert-butylhydroxy-5'-hydroxyacetopentanone, obtained in the same manner as in Reference Example 3, and 22.9 g of 2-aminoviridine t

Dissolve in 450 ml of ethanol, and stir at room temperature for 18:00. 125 ml of water is added to the reaction mixture, and the mixture is stirred for 1 hour. The precipitated crystals are collected by tt and washed with a mixed solvent (ethanol: water = 1: 1), and then with a small amount of ether. Dissolve the crude crystals in 600 ml of ethanol while heating, and add 120ffll of hot ice. After cooling, the precipitated crystals were collected and dried to give 27.3 g of the desired compound as pale yellow crystals.

 ¾ point 192 〜: L94 t

Elemental analysis (as C _I7 H ₁₇ IN ₂₀ )

 As per theory (%) C: 52.06 H .37 Ν: 714

 Actual surveyor (%) C-51.88 Η: 4.17 Ν: 7.10

 To 0.5 g of the crystals obtained above, 30% methanolic hydrochloric acid is added and dissolved by heating. Ether was added, and the precipitated crystals were collected, washed with ether, and dried to obtain 0.49 g of a silicate.

 Break 207 〜2Q9 t

Elemental析儘(as _{C 17 H ie ClIN 2 0 ·} 3 / 4Η 3 0)

 镲 (%) C 6.17 Η: 4.44 Ν: 6.33

 Measured 值 (%) C: 46.35 H: 4.51 K: 6.28

 The following compounds were produced in the same manner as in Examples 1-2.

Example 3

 2- (3-tert-butyl-5-chloride π-xyphenyl) imidazo

 [1,2-a] viridin

 200-201 X

Elemental析惶(as C ₁₇ H ₁₇ C1N ₂ 0)

 Theoretical plant (%) C: 67.99 H: 5.69 N: 9.35

Observed child (%) C: 67.88 H: 5.70 N: 9.31 Example 4

 2- (3-tert-butyl-5-fluoro mouth-4-hydroxyphenyl) imidazo

 [1,2-a] bilidine

 Cut point 232 to 233 t

Elemental analysis (as C ₁₇ H ₁₇ PN ₂₀ )

 Theoretical plant (%) C: 71.81 Η: 6.003 Ν: 9.85

 Measured 值 (%) C: 71.81 H: 6.29 N: 9.68

Example 5

 2- (3-butamo-5-tert-butyl-4-hydroxyphenyl) -6-methylmidazo [1,2-a] viridine

 Melting point 181-182 n

Elemental析值(as C _ie H ₁₈ BrN ₃ 0)

 Theory 值 (%) C: 60.18 H: 5.33 N: 7.80

 Actual measurement (%) C: 60.12 Η: 5 · 37 Ν: 7.78

Example 6

 2- (3-butamo-5-tert-butyl-4-hydroxydiphenyl) -8-methylimidazo [1,2-a] viridine

 With a melting point of 185-187

Elemental analysis value (as C _ie H _ls BrN ₂₀ )

 Theory 值 (%) C: 60.18 H: 5.33 N: 7.80

 Measured 值 (%) C: 60.16 H: 5.43 N: 7.63

Example 7

2- (3-Bumo-5-tert-butyl-4-hydroxyphenyl) -6-cycloimidazo [1,2-ai] viridine 戬 point .UQ ~ 143:

Elemental Analysis H (as C ₁₇ H _ie BrClIi ₂ 0)

 Theoretical plant (%) C: 53.78 H: 4.25 N: 7.38

 Measured 谊 (%) C: 53.76 H: 4.37 N: 7.31

Implementation 锊 8

 2- (3-bromo-5-tert-butyl-4-hydroxyphenyl) -6,8-dibromoimidazo [1,2-a] viridine

 ¾ point 20.9 to 210.5 t

Elemental analysis (as C ₁₇ H _ls Br ₃₀ )

 Theory (%) C: 40.59 H: 3.01 N = 5.57

 As measured (%) C: 40.42 Η: 29797 Ν: 5 · 53

Implementation 锊 9

 2- (3-Bumo-5-tert-butyl-4-hydr π-xyphenyl) -3-methylimidazo [l, 2-a] pyridine

 Cut point 200 to 200.5 t

Elemental析值(as C _le H _ls BrN ₂ 0)

 Theoretical (%) C: 60.18 Η: 5.33 Ν: 7

 Measured 镣 (%) C: 59.96 H: 5.32 N: 7.66

Implementation 锊 10

 2- (3-butamo-5-tert-butyl-4-hydroxyphenyl) -3,6-dimethylimidazo [l, 2-a] viridine

 Melting point 221-221.5 t

Elemental analysis planted _{(C ls H al BrN 2 (} ] as)

Theory (%) C: 61.13 H: 5.67 N: 7.50 Actual measurement (%) C: 60.81 H: 5.90 N = 7.31

Example 11

 2- (3-ter_t-butyl-4-hydroxy-5-hydroxyunyl) -6-methylimidazo_ [1,2-a] viridine

 S point 180 to 182 t

Elemental analysis II (as C _ie H ₁₃ IN _a [))

 Planting (%) C: 53.22 H: 4, 71 N: 6.90

 Rut Sweet Plant (W) C: 53.29 Η: 5 · 15 «: 6.92

Example 12

 2- (3-tert-butyl-4-hydridoxy-5-phosphorinyl) -6-chloromidazo [1,2-a] viridine

 ¾ point 169-171 t

Elemental析僂(as C ,, H _ie ClIN ₂ 0)

 Theory 值 (%) C 7.85 H: 3.7B N: 6.57

 Actual measurement (%) C: 47.94 HM.00 N: 6.49

Example 13

 2- (5-tert-butyl-3-cyclo mouth-4-hydroxyphenyl) -6-methylimidazo [1,2-a1 viridine

 Melting point 188 ~ 190

Elemental analysis (as C _ie H _ls ClN ₂₀ )

 Theory 值 (%) C = 68.68 H: 6.08 N: 8.90

 Actual measurement (%) C: 68.64 Η: 6.10 Ν: 8.995

Example U

2- (5-tert-butyl-3-3-chloro-4-hydroxy-t-nil) -6-k Midazo [1, 2-a] viridine

 Toshiki points 149 to 151

Elemental analysis 镲 (as [ _ι7 Η _1Β Π ₃ ίΙ ₂ [])

 Theory (%) G: 60.91 H: 4.81 N: 8.36

 Real fashion (%) C: 60.92 H: 4.89 N: 8.44

Example 15

 2- (3-tert-butyl-4-hydr α xyphenyl) midazo [1, 2-a]

 With a melting point of 280-282

Elemental Analysis planting (as C ₁₇ H _ie N ₂ 0)

 Theory (%) C: 76.66 Η: 6.81 ΝΠΟ.52

 Actual measurement (%) C: 76.68 H: 6.94 N: 10.25

Example 16

 2- (3-tert-butyl-4-hydraxy-5-methoxyphenyl) imidazo

 [1,2-a] bilidine

Kazutoshi point 183-184 - elemental analysis planting (as _{C ie H 2O N 2 0 2} )

 Science plant (%) C: 72.95 H: 6.80 N: 9.45

 C: 73.01 Η: 7 · 17 Ν: 9.37

Example 17

 2- (3-chloro-5-tert-butyl-4-hydroxyphenyl) -8-hydroxymidazo [1.2-a] viridine

 Melting point 212-214 -C

Analyze the following (as d, H ClNaQs) Theory 镓 (%) C: 64.46 H: 5.41 N: 8.84

 Actual surveyor (%) C: 64.32 H: 5, 53 N: 8.62

Prescription example 1

 50 mg of the compound of Example 2

 Lactose 46 mg

 Corn ¾ flour 20 mg

 Hydroxyb mouth with low degree of substitution Virucellulose 8 nig

 Head σXiv mouth Virmethylcellulose 5 mg

 Magnesium stearate 1 oig

 130 rag in total

After uniformly mixing the above ingredients except hydroxypropyl n-methylmethylcellulose and magnesium stearate, for tableting by wet granulation using aqueous solution of hydroxyvirville methylcellulose 8X (w / _W ) as a binder Produce granules. After mixing magnesium stearate with this, it is molded into a tablet with a diameter of 7πκη and a weight of 130 mg using a tableting machine.

Prescription example 2 5 times

 200 mg of the compound of Example 2

 Mannitol 220 mg

 Hydroxyb 13 Virucellulose 40 mg

 Containing silicon dioxide 10 mg

 1000 mg in total

Mix the above formulation ingredients with hydroxymethyl mouth Mix. This was subjected to wet granulation using an aqueous solution of π- xypropylcell tD-source 8 (w / w) as a binder to obtain a granule. Test Examples The results of pharmacological tests showing the usefulness of typical examples of the compound of the present invention are shown below. The existing representative anti-inflammatory drug was used as a control drug. Compounds described in the literature were used as comparative compounds. Test method

 1. Inhibition of pi-staglandin biosynthesis

10¾ calf serum containing Darube' co variant b Guru培蹇solution (hereinafter abbreviated as DMBM) in and, after 24 hours of incubation the Usagi cartilage钿胞(5 x 10 ^s偭), the culture solution [1- ^{1 4} [C] -Rachidonic acid (18.5 Bq) was replaced with a DMBM culture solution. After culturing for 18 hours, the cells were washed twice with DMBM, and the culture solution was replaced with a culture solution containing interα-kin-l (I Ll) (100 units / ral) and a test drug. After 24 hours of ffi culture, 1N hydrochloric acid was added to the culture supernatant, extracted twice with ethyl acetate, and the extract was evaporated to dryness. The residue was redissolved in a small amount of sulfuric acid:!: Chill and spotted on a thin gel sheet. After development, the radioactive sites were measured using a chromatogram scanner. Cut a portion corresponding to Burosutagura Nji down _82, and measured the radioactivity. The results are shown in Table 1.

Test drug Egret in tfc bone cells

 PSE, biosynthesis inhibitory action

IC ₅ a (U) Example 2 5. 6 X IO ^"9

 Indomethacin 1.2 X10- '

Diklov Unak Ha 7.3 XIO " ⁸ As is clear from Table 1, the compound of the present invention has a brostaglandin biosynthesis inhibitory action equal to or higher than that of the control drug, and is expected to have an anti-inflammatory action.

 2. Reactive oxygen production inhibitory action

Guinea pigs were intraperitoneally injected with 2X casein, and after 16 hours, peritoneal exudate leukocytes were collected and 10 mM [N- (2-hydroxyxetil) bidirazine-N, -2-ethanesulfonic acid] (HBPBS) A leukocyte suspension was prepared with mild street solution (PH7.4). The reaction was initiated by the simple incubation of a leukocyte suspension (2 x 10 ⁶ leukocytes) containing luminol and the test drug at 37 "C for 5 minutes, followed by the addition of ovosoninated zymosan. The chemiluminescence intensity after the start was measured using a fluorimeter, and the results are shown in Table 2.

Table 2

 As is evident from Table 2, the compound of the present invention has an active oxygen production inhibitory effect that is 50 times or more superior to that of the control drug.

 3. 5-lipoxygenase inhibitory action

An enzyme solution prepared from guinea pig leukocytes and a 50πι phosphate buffer (containing 7.4 mM, 2rai4 CaCl _a , 2 mM glutathione and 2 mM adenosine 5'-triphosphate) containing the test drug were used. in * 0, then 5 minutes Lee Nkyu base over preparative, [1 - the addition of ¹ Ryo Lucky Don acid (370 Bq / ml) / JP93 / 00309

 3 2

 To start the reaction. After 10 minutes, the reaction was stopped by adding 0.3% citric acid. After extracting twice with ether, evaporating to dryness, the residue was redissolved in a small amount of chloroform / methanol (2/1) and spotted on silica gel thin plates. After development, the radioactive site was measured using a chromatogram scanner, and the portion corresponding to 5-hydroxy-6, 8, 11, 14-eicosatetranic acid (5-HETB) was cut out and the radioactivity was measured. It was measured. Table 3 shows the results.

Table 3

 As is clear from Table 3, the compound of the present invention has an excellent 5-lipoxygenase inhibitory activity not found in the control drug.

 4. Inhibition of bone resorption in rat fetal long bones

Under ether anesthesia, 45Ca (CaCl ₂ , 3.7 Bq) was injected subcutaneously into the rat on the 18th day of pregnancy. Eighteen hours later, the fetus' radial bone was excised, and the epiphyseal cartilage was excised to obtain a long bone specimen, which was pre-cultured in BGJb culture solution (bovine serum albumin). On the next day, the culture solution pre-cultured was replaced with a culture solution containing lipopolysaccharide (LPS) $ ίί intense macrophage culture * supernatant and a test drug (BGJb culture broth), and further cultured for 96 hours. After incubation, the solution was dissolved in 1N hydrochloric acid for ^<5 Ca to residual exist in long bone specimens with T the liberated ^{4 5} Ca is the radioactivity in the culture solution, * ^s Ca was遊雜in culture Was calculated. Table 4 shows the results. 93 1

 3 3

Table 4

 As is clear from Table 4, the compound of the present invention has an excellent bone resorption inhibitory action not found in the control drug.

 5. Inhibitory effect of IL-1 on the growth of human latent

Chronic闋節Li Umachi patient Namera胰cells (10 ⁴⁾ were cultured in I Ll (100pg / ffll) and Dulbecco's modified method Iguru medium containing the test drug (10X calf serum-containing), a K-th time 66 ^a H-thymidine (18.5 kBq) was added, and the cells were further cultured for 6 hours. After completion of the culture, the radioactivity of ³ H-thymidine incorporated into synovial cells was measured. Table 5 shows the results.

Table 5

 As is evident from Table 5, the compound of the present invention has an excellent inhibitory action on the growth of human slip which is not seen in the control drug.

 6. Effects on collagen arthritis

 (1) Production of collagen arthritis

ゥ Dissolve (2 ng / ral) collagen type II collagen derived from articular cartilage in 0.1 M acetic acid saline solution, and mix in equal volume with complete mouth infusion adjuvant (CFA) The primary sensitization was performed by injecting 0.1 ml of the emulsion into the skin of the tail of the mouse. The first sensitization day was set to day 0, and the second sensitization was performed by injecting subcutaneously the back of the mouse on the 21st day with an emulsion E.lnl of an equal volume of type II collagen solution and CPA prepared in the same manner as the first sensitization. went.

 The test drug was orally administered once a day from the first cropping day until the 34th day for 35 days.

 (2) Effects on deer swelling

 Up to 35 days after the primary sensitization, changes in B-node inflammation were visually observed.

 (3) Effects on joint lesions

 1) X-ray examination

 On day 35, the limbs were imaged using an X-ray photography apparatus.

 2) Histopathological search

 — On day 35 after the next sensitization, the limb of the mouse was cut, a tissue specimen was prepared, and observed under a microscope.

 The compound of Example 2 suppressed all items, and the minimum effective dose was lOrag / kg.

 7. Gastric injury

Male rats (SD strain, 6-week-old) were grouped into 6 rats, each of which was used at 24 hours before the administration of the test drug. The test drug was dissolved or suspended in an ice solution of methylcellulose and administered in a syringe. Seven hours after administration of the test drug, the stomach was removed, 10 ml of formalin solution was injected into the stomach, and the stomach was immersed in ^ formalin solution and fixed. Ten minutes after formalin fixation, the stomach was dissected along the bay and the stomach was observed using a stereomicroscope. Table 6 shows the results. Table 6

 As is clear from Table 6, the compound of the present invention can be said to be a drug with very little damage to the gastric mucosa and little risk of side effects.

 8. Acute toxicity

 Male rats (SD strain, 5 years old) were used as 4 rats per group. Seven days after administration of the drug β-mouth, the presence or absence of survival was observed. No death occurred in the compound of Example 2 at a dose of 2,000 mg / kg.

 9. Action to block IL-1 release from human peripheral blood monocytes

 The experiment was carried out according to the method of R. Rudolf-Adara et al. (Drugs Bxp. Clin, Res. 8_ · 355-362 (1989)).

Present compound (the compound of Example 2) and 2- (3, 5-di -tert- butyl-4-arsenide Dorokishifu _Λ sulfonyl) Lee Midazo [1, 2-a] kink Jin (A Comparative compound) to be联薬product And

Mononuclear cells were separated from healthy human peripheral blood by the PicoU-Hypaque overlay method, dispersed in RPMI-1640 culture broth, and then seeded on a 96-well culture plate at 2xlO ^s. did. Two hours later, each well was washed with RPMI-1640 to remove non-adherent cells, and the adherent cells were subjected to the experiment. The drug and RPMI-1640 supplemented with 2% calf serum were added to each well, and cultured for 1 hour. Then, lipopolysaccharide (1 （g / ml) was added. After culturing for 16 hours, the culture supernatant was collected and IL-1 contained therein was quantified by a sodium immunoassay. Table 7 shows the results. Table 7

 * P <0.05

 While the comparative compound has no inhibitory effect on IL-1 release, it is clear that the compound of the present invention has an inhibitory effect on IL-1 migration and contributes to an inhibitory effect on joint destruction.

 10. Gastric Stimulation Inhibitory Compounds of the Invention (Compound of Example 2) and 2- (3,5-di-tert-butyl-4-hydroxyphenyl) imidazo [1,2-a] viridine ( The same experiment as above was performed using the comparative compound as a test drug, and the results are shown in Table 8. Table 8

* P-0.05 P-0.01 It is clear that the comparative compound has a clear gastric mucosal damage effect and cannot be used as a pharmaceutical. From the above test results, the compounds of the present invention are not only effective in inhibiting inflammation, but also have a good balance of cyclooxygenase and lipoxygenase activity inhibitory effects, and are known as existing anti-inflammatory agents. No inhibitory effect on IL-1 migration, inhibitory effect on synovial growth and bone resorption by IL-1 It can be seen that it has an action (section 披 inhibitory action). Furthermore, it has an inhibitory effect on the production of active oxygen by polymorphonuclear leukocytes, and thus can stop the progression of rheumatoid arthritis. In addition, it suppresses arthritis induced by adjuvant or type II collagen and has few side effects such as gastrointestinal disorders, so it can be safely used for chronic rheumatoid arthritis.

Claims

Scope of request 1. An imidazo [1,2-a] viridine derivative represented by the following general formula [I] and a pharmacologically acceptable salt thereof. [I]

In the formula, R ¹ represents chromium or alkyl, and R ^a and R ^s are the same or different and represent arsenic, alkyl, hydroxy, alkoxy or halogen. X represents hydrogen, halogen, or alkoxy. ^{2. R l, R 2, R} 3 is A compound according to claim 1, wherein the X Gaha α Gen hydrogen.  3. (3-tert-butyl-4-hydroxy-5-iodophenyl) imidazo [1,2-a] pyridine or a pharmaceutically acceptable salt thereof.  4. A therapeutic agent for rheumatoid arthritis, comprising the compound according to claim 1 as an active ingredient.