WO1999045002A1 - Benzofuran derivatives - Google Patents

Abstract

Benzofuran derivatives represented by formula (I) or pharmacologically acceptable salts thereof: wherein R1 represents hydrogen, optionally substituted lower alkyl, lower cycloalkyl, etc.; R?2, R3, R4 and R5¿ are the same or different and each represents hydrogen, lower alkyl, optionally substituted aryl, optionally substituted aralkyl, etc.; R6 represents hydrogen, lower alkyl, etc.; R?7 and R8¿ are the same or different and each represents hydrogen, lower alkyl, optionally substituted aryl, etc.; R9 represents optionally substituted lower alkyl, etc.; and A represents lower alkyl, optionally substituted aryl, etc.

Description

 Details

 '' Derivative technology field

 The present invention relates to a benzofuran derivative having an autoimmune disease suppressing effect.

Background technology

 Conventionally, benzofuran derivatives are industrially useful, and patents have been disclosed as intermediates for production raw materials, light-emitting elements, pesticides, anthelmintics, pharmaceuticals, and the like.

 J. Med.Chem., 31, 84-91 (1988), JP-A-61-50977, JP-A-61-126061, JP-A-61-143371 and JP-A-62-230760 describe a carboxyl group or tetrazolyl. Disclosed are a benzofuran derivative, a benzopyran derivative and a benzodioxole derivative having a group, and it is described that these have a leukotriene antagonism, a phospholipase inhibitory action, a 5α-reductase inhibitory action, an aldose reductase inhibitory action, and the like. WO92 / 01681 and W092 / 12144 disclose benzofuran derivatives and benzopyran derivatives having an inhibitory action on acyl-CoA acetyltransferase (ACAT). Also,

WO93 / 01169 discloses a benzofuran derivative having an antikinetic action. EP307172 and US4910193 disclose benzofuran derivatives having serotonin 3 (5HT ₃ ) receptor antagonism. Bioorganic Med.Chem. Lett., 14, 1855-1860 (1994), EP685479, WO96 / 03399,

W096 / 36626, W096 / 36625, WO97 / 20833 include phosphodiesterase

 A benzofuran derivative having (PDE) -IV inhibitory activity, W096 / 36624, reports an oxygen-containing heterocyclic compound having PDE-IV inhibitory activity.

Disclosure of the invention

 An object of the present invention is to provide a benzofuran derivative having an excellent autoimmune disease suppressing effect.

The present invention provides a compound of the formula (I) (I)

 ~

. , AR ^J

(Wherein Ri represents a hydrogen atom, substituted or unsubstituted lower alkyl, lower cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl, and R ² , R ³ , R ⁴ and R ⁵ represent Same or different hydrogen atom, lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkyl, lower cycloalkanol, substituted Or unsubstituted arylo, lower alkoxyl, luponyl, cyano, carboxy, halogen, substituted or unsubstituted amino or substituted or unsubstituted carboxamide, and R ⁶ is a hydrogen atom, lower alkyl or substituted or unsubstituted aryl. the stands, R ⁷ and R ⁸ are taken the same or different hydrogen atom, a lower a Kill, substituted or unsubstituted Ariru, represents lower alkoxy or halogen, R ⁹ represents a substituted or unsubstituted lower alkyl, substituted or unsubstituted § re Ichiru, substituted or unsubstituted a Ararukiru or pyridyl alkyl, A represents lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted pyridyl) or a pharmaceutically acceptable salt thereof.

 Hereinafter, the compound represented by the formula (I) is referred to as compound (I).

In the definition of each group of the formula (I), the lower alkyl moiety of lower alkyl, lower alkoxy, lower alkoxycarbonyl and lower alkanoyl may be a straight-chain or branched C1-C8 alkyl group such as methyl, Includes ethyl, propyl, isopropyl, butyl, isobutyl, isooctyl, see-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like. The cycloalkyl moiety of lower cycloalkyl and lower cycloalkanoyl includes those having 3 to 10 carbon atoms, for example, cyclopropyl, cyclohexyl, cyclooctyl, cyclodecyl and the like. It is.

 Aralkyl includes C7-C15, for example, benzyl, phenethyl, benzylhydryl, naphthylmethyl and the like. Examples of aryl include phenyl, naphthyl, indenyl, biphenyl, anthryl and the like. Benzoyl, toluoyl, naphthoyl, phthaloyl, etc. are included as aroyl. The alkyl part of the pyridylalkyl has the same meaning as the lower alkyl.

 Halogen includes fluorine, chlorine, bromine and iodine atoms. Substituted lower alkyl, substituted aryl, substituted aralkyl, substituted lower alkoxy, substituted lower alkanol, substituted aroyl and substituted pyridyl have the same or different substituents, and have 1 to 3 substituents, for example, lower alkyl, lower alkoxy, halogen, etc. Is included. Here, the definitions of lower alkyl, lower alkoxy and halogen are as defined above.

Substituents of substituted amino and substituted lipoxamide include substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and 5 to 7 members formed including nitrogen atom. Or a substituted or unsubstituted heterocyclic group. Here, the substituted or unsubstituted lower alkyl, the substituted or unsubstituted aryl, the substituted or unsubstituted aralkyl are the same as those described above, and the substituted or unsubstituted substituted or unsubstituted aryl group containing a nitrogen atom and having 5 to 7 members is formed. Examples of the telocyclic group include morpholino, piperidino, piperazinyl, homopirazinyl, N-methylbiperazinyl, N-benzylhomopiperazinyl and the like. Pharmaceutically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. . Pharmaceutically acceptable acid addition salts of compound (I) include inorganic acid salts such as hydrochloride, sulfate, nitrate and phosphate, acetate, maleate, fumarate, citrate, and tartaric acid. Organic salts such as salts, etc .; pharmacologically acceptable alkali metal salts and alkaline earth metal salts include sodium salts, potassium salts, calcium salts, etc .; pharmacologically acceptable salts Ammonies Examples of the salt include ammonium, tetramethylammonium, etc., and pharmaceutically acceptable organic amine addition salts include morpholine, piperidine, etc., and pharmaceutically acceptable amino acids. Examples of the addition salt include addition salts such as lysine, daricin, and feniralanine.

 In the production of compound (I), intermediates and target compounds are isolated by purification methods commonly used in synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various types of chromatography. It can be purified. Further, the intermediate can be subjected to the next reaction without purification.

 When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it can be purified as it is. It should be done.

 Compound (I) and its pharmacologically acceptable salts may be present in the form of adducts with water or various solvents. These adducts are also usefully used for the purpose of the present invention. be able to.

 Some of the compounds (I) may have geometrical isomers, optical isomers, etc. in terms of stereochemistry, but all possible stereoisomers of the compound (I) and mixtures thereof are also included in the present invention. It can be used as a compound.

 Next, a method for producing the compound (I) will be described.

 Compound (I) can be produced by the following production method. However, it is not limited to the following production method.

Process 1

(Wherein, R ¹ , R ² , R ³ , R 4, R 5, R 6, R 7, R 8 and R 9 are each as defined above. Is)

 The starting compound (II) can be obtained according to a known method [J. Med. Chem., 30, 62-67 (1987)].

 Compound (IV) can be obtained by a dehydration condensation reaction between raw material compound (II) and aniline (III). Many methods are known for this dehydration condensation reaction [Refer to Maruzen, 4th Edition, Experimental Chemistry, Vol. 22, p. 138 (1990)], and can be applied. For example, compound (Π) can be prepared by adding 1 equivalent to a large excess of thionyl chloride, oxalyl chloride or phosphorus pentachloride in an inert solvent or in the absence of a solvent. ~ 5 minutes to 10 hours at a temperature between the boiling point of the solvent used to lead to the corresponding acid chloride, and then 1 equivalent to a large excess of aniline (III) in an inert solvent. If necessary, the reaction can be carried out at a temperature between -50 ° C and the boiling point of the used solvent for 5 minutes to 10 hours in the presence of 1 equivalent to an excess of a base. Also, if ethyl ethyl formate or the like is used instead of thionyl chloride or the like, a mixed acid anhydride can be obtained instead of the acid chloride. The corresponding mixed acid anhydride of compound (II) can also be reacted with aniline (III) in the same manner as acid chloride to lead to compound (IV).

 The bases used in the reaction of thionyl chloride, oxalyl chloride or phosphorus pentachloride are triethylamine, diisopropylamine, triptylamine, dicyclohexylmethylamine, N-methylmorpholine, N-methylbiperidine, diazabicyclo Examples include undecene (DBU), diazabicyclononene (DBN), and pyridine.

 Bases used in the reaction of aniline (III) include sodium hydroxide, potassium hydroxide, sodium methoxide, potassium ethoxide, sodium hydride, potassium hydride, butyllithium, lithium diisopropylamide (LDA), potassium tert- Examples include butoxide, triethylamine, N-methylmorpholine, N-methylpiperidine, DBU, DBN, pyridine and the like.

Inert solvents used in both reactions are tetrahydrofuran (THF), Examples include dioxane, getyl ether, ethylene glycol, glyme, diglyme, methanol, ethanol, butanol, isopropanol, dichloromethane, chloroform, benzene, toluene, dimethylformamide (DMF), dimethylsulfoxide (DMSO), and the like. .

Process 2

(Wherein, I ¹ , R ² , R3, R4, R5, R6, R7, R8, R9 and _A are as defined above)

 Compound (I) can be produced by acylating compound (IV). Many methods are known for the acylation of aromatic compounds [Refer to the fourth edition of Experimental Chemistry, Vol. 22, p. 278 (1990) Maruzen], and are applicable. For example, compound (IV) can be prepared by reacting compound (IV) in an inert solvent, preferably a halogen-based solvent such as dichloromethane, in the presence of 1 equivalent to a large excess of acid chloride (V) and 1 equivalent to a large excess of an acid. The desired compound (I) can be obtained by reacting at a temperature between the boiling points of the solvents used in 50 to 5 minutes to 48 hours.

 Examples of the acid include methanesulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, boron trifluoride, aluminum chloride, stannic chloride, titanium tetrachloride, zinc chloride, ferric chloride and the like.

 Examples of the inert solvent include THF, dioxane, getyl ether, ethylene dalicol, triethylene glycol, glyme, diglyme, dichloromethane, chloroform, benzene, and toluene.

The structure of a typical example of the compound (I) is shown below.

 Compound 1 Compound 2

 Next, the pharmacological action of the compound (I) will be specifically described with reference to test examples. Test Example 1: Prophylactic effect on rat adjuvant arthritis

 The preventive effect on rat adjuvant arthritis was measured by the following method.

Eight-week-old male Lewis rats (Charles River Co., Ltd.) were used, and each group consisted of eight rats. According to the method of Newbould BB [Brit.J.Pharmacol. (Brit.J.Pharmacol), 127 (1963)], killed mycobacterium butylicum cells suspended in liquid paraffin (Difco Using 0.66 mg / 0.1 ml as an adjuvant, rats were injected subcutaneously into the right hind paw of a rat whose volume was previously measured. After the treatment, the volume of both hind limbs was measured using a rat hind limb paw edema volume measuring device (UNICOM TK-101) and compared with the volume before the treatment.

 Test compound (Compound 1) 30 mg / kg was suspended in a 0.5% methylcellulose solution and administered intraperitoneally once a day on Day 0-4, Day 7-11 and Dayl4-16 on the day of adjuvant treatment as Day O .

 The control group received a 0.5% methylcellulose solution intraperitoneally.

 Cyclosporin A (CysA), which is recognized as a typical immunosuppressant, was used as a comparative compound.

 The results are shown in FIGS.

 Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. The pharmaceutical preparations are used for animals and humans.

The pharmaceutical preparation according to the present invention comprises the compound (I) or its pharmacology as an active ingredient. Pharmaceutically acceptable salts alone or as a mixture with any other therapeutically active ingredient. In addition, such pharmaceutical preparations are produced by mixing the active ingredient with one or more pharmaceutically acceptable carriers and by any method well known in the technical field of pharmaceuticals.

The active ingredients to be mixed are: serotonin 3 (5HT ₃ ) receptor antagonist, serotonin 4 (5HT ₄ ) receptor antagonist, serotonin 1A (5HTIA) receptor agonist, dopamine 2 (D ₂ ) receptor antagonist And histamine 1 receptor antagonist, muscarinic receptor antagonist, neurokinin 1 receptor antagonist, endothelin A (ET _A ) receptor antagonist and the like.

 The route of administration is preferably the one that is most effective in treatment, and may be oral administration or parenteral administration, for example, oral, respiratory, rectal, subcutaneous, intramuscular, intravenous, etc. .

 Dosage forms include sprays, capsules, tablets, granules, syrups, emulsions, suppositories, injections, ointments, tapes and the like.

Liquid preparations suitable for oral administration, e.g., emulsions and syrups, include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, and oils such as sesame oil, olive oil and soybean oil. , P-hydroxybenzoic acid esters and the like, and preservatives such as strawberry flavor, peppermint and the like. Capsules, tablets, powders, granules, etc. are excipients such as lactose, glucose, sucrose, mannitol, disintegrants such as starch, sodium alginate, lubricating agents such as magnesium stearate, talc, etc. A suitable formulation for parenteral administration can be prepared using a binder, a binder such as polyvinyl alcohol, hydroxypropylcellulose, and gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin. It consists of a sterile aqueous preparation containing the active compound which is isotonic. For example, in the case of an injection, a solution for injection is prepared using a carrier comprising a salt solution, a glucose solution, or a mixture of saline and a glucose solution. Formulations for enteral administration include, for example, cocoa butter, hydrogenated fat or It is prepared using a carrier such as boric acid and provided as a suppository. The propellant is prepared using a carrier or the like which does not irritate the active compound itself or the mucosa of the mouth and respiratory tract of the recipient and disperses the active compound as fine particles to facilitate absorption. Specific examples include lactose and glycerin. Formulations such as aerosol and dry powder are possible depending on the nature of the active compound and the carrier used.

 Among these parenteral preparations, one selected from the diluents, flavors, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. exemplified for the oral preparations Alternatively, more auxiliary components can be added.

 The effective amount and frequency of administration of compound (I) or a pharmaceutically acceptable salt thereof will vary depending on the form of administration, the age and weight of the patient, and the nature or severity of the condition to be treated. In this case, O.Olmg ~: lg, preferably l ~ 500mg per adult is administered once or several times a day. In the case of parenteral administration such as intravenous administration, 0.001 to! OOmg, preferably 0.01 to! Omg per adult is administered once or several times a day. However, these dosages vary depending on the various conditions described above.

BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 shows changes in right hind limb paw volume after adjuvant treatment. The horizontal axis represents the number of days of drug administration (days), and the vertical axis represents the right hind paw volume (ml) of the rat.

 Fig. 2 shows changes in left hind paw volume without adjuvant treatment. The horizontal axis represents the number of days of drug administration (days), and the vertical axis represents the left hind paw volume (ml) of the rat.

 The reference numerals used in FIGS. 1 and 2 are as follows.

I □ ~: Control group

 Test compound administration group

 Comparative compound administration group

 -0— one.

Next, examples of the present invention and formulation examples will be given ₍

BEST MODE FOR CARRYING OUT THE INVENTION Example 1: 4-methylcarbonyl-7-methoxy-1-N-phenylbenzofuran-2-carboxamide (Compound 1)

First step: The starting compound 7-methoxybenzofuran-2-carboxylic acid [J. Med. Chem., 30, 62-67 (1987)] (30 g) is dissolved in dichloromethane (450 ml), and oxalyl chloride (20.4) is dissolved. ml) and the mixture was stirred at room temperature for 15 hours. The residue obtained by concentrating this under reduced pressure was dried to obtain the corresponding acid chloride (33 g). The acid chloride (I0g) was dissolved in THF (330ml), and triethylamine (13.2ml) and aniline (6.5ml) were added, followed by stirring at room temperature for 1 hour. The reaction solution was diluted with 1N hydrochloric acid (400 ml), and the organic layer was extracted with ethyl acetate, and further washed with 1N hydrochloric acid. This was dried over magnesium sulfate, filtered and concentrated under reduced pressure. To the residue was added chloroform, and trituration gave 7-methoxy-N-phenylbenzofuran-2-carboxamide (compound la) (12.4 g, 98%) as a colorless solid.

_{NMR (CDC1 3, 6ppm):} 3.97 (s, 3H), 6.88 (dd, IH, J = 2Hz, 7Hz), 7.1-7.25 (m, 3H), 7.35 (dd, 2H, J = 8Hz, 8Hz), 7.55 (s, IH), 7.71 (d, 2H, J = 8Hz), 8.51 (bs, IH). MASS (m / z): 267 (M ⁺ ).

Second step: The obtained compound 1a (I2.7 g) was dissolved in dichloromethane (240 ml), and acetyl chloride (6.4 ml) and titanium tetrachloride (19.9 ml) were added thereto, followed by stirring at room temperature for 2 hours. . The reaction solution was poured into a cooled diluted hydrochloric acid solution, and the organic layer was extracted with ethyl acetate. This was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: 1% methanol / monochrome form), and recrystallized from ethanol to obtain Compound 1 (3.86 _g , 28%) as a colorless solid.

NMR (DMSO-d _6> δρριη): 2.51 (s, 3H), 4.09 (s, 3H), 7.15 (t, IH, J = 8Hz), 7.20 (d, IH, J = 8.5Hz), 7.39 (dd , 2H, J = 8Hz, 8Hz), 7.83 (d, 2H, J = 8Hz), 8.06 (d, IH, J = 8.5Hz), 8.40 (s, IH).

MASS (m / z): 309 (M +), 294, 217. π 畺 ¾ 氺 ^ 榜

τ呦 :^ 鹏鎩 S ^m ox τ rinse;! : — ^ — ^ Job

τ 呦: ^ 鹏 鎩

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 'HS' Ρ) 96 · 9 '(HS's) 90' '(HS's) 9 S' (HS's) 0L'8: (^ ddg '9p-.S-picture) 丽 N ¾¾¾, §9 · ε) z ^ π 口 ^ Ψ ^ Ι ^ -s

'(HT' ^s q) XS ^, 8 '(zH6 = f' HS 'Ρ) ΐ9''(HI ^) Z ^ L' (RZ ^) 9Z'L- VL '(HS' ra) 6'9- 8'9 '(HS' s) L6-8 '(HS ^) LLS: (mdd' ειοαθ) ΗΙ [Ν

：： 固 ¾¾¾ (% S6

 (2 ェ 乙-^-) -Ν- ^ Φ4 ^ -L, 1 ¾¾ ^ 2-a a

c-ί ： ZMM

c-ί: ZMM

09-f: N 'ZQ-f Ή' 6 ^ 69 Ό ^: (%) Listen 68 ^: N '' Ψ Ή '88 * 69: (%) picture

0¾Τ ・ ^ ΟΝ ^2ΐ Η ^8ΐ Ο Mine 600 / 66df / I.3d r00SW66 OAV 1.0ml

Formulation Example 2: Suppository

 Finely pulverized Compound 1 is mixed with a molten suppository base, poured into a mold and cooled to obtain a suppository.

 Ingredient Per suppository

 Compound 1 10 mg

 Cocoa butter (base) suitable amount

 2.0g

Formulation Example 3: Syrup

 Mix ethanol, sucrose, sodium benzoate, methylparaben and fragrance with 70% of the total water. Mix iron sesquioxide and compound 1 with the rest of the water, then mix the two solutions to give a mouthwash.

 Component per 1ml

 Compound 1 10 mg

 0.3mg of ethanol

 2.0mg sucrose

 0.5mg

 Sodium benzoate 0.5mg

 Cherry flavoring

 Ferric oxide

 water

 1.0ml

Formulation Example 4: Tablet

 A finely powdered compound 1 is mixed with powdered potato starch, lactose, magnesium stearate, polyvinyl alcohol and tar pigment, and then compressed to form tablets.

Ingredient Per tablet Compound 1 lOOmg

 Lactose 60mg

 Potato starch 50mg

 Polyvinyl alcohol 2mg

 Lmg magnesium stearate

 Evening dye

Formulation Example 5: Capsule

 Mix finely ground Compound 1 with powdered lactose and magnesium stearate. The mixture is filled into gelatin capsules to obtain capsules.

 Component per capsule

 1 dOOmg

 Lactose 540mg

 Lmg magnesium stearate

Formulation Example 6: powder

 Finely pulverized Compound 1 and powdered lactose are mixed to obtain a powder.

 Ingredient per packet

 Compound 1 lOOmg

 Lactose 240mg

Formulation Example 7: Nasal drops

 Dissolve the preservative in warm purified water and allow to cool. Add sodium chloride and finely ground compound 1. Adjust the pH to 5.5-6.5 and dilute with purified water to a final volume of 100 ml to obtain nasal drops.

 Per 100 ml of component

 Compound 1 lOOmg

 Sodium chloride 800mg

 Methyl paraoxybenzoate 500mg

purified water 100 ml

Formulation Example 8: Eye drops

 Adjust in the same manner as nasal drops to obtain eye drops.

 Ingredient per 100ml

 Compound 1 lOOmg

 Sodium chloride 800mg

 Methyl paraoxybenzoate 500mg

 Purified water qs

 100ml

Formulation Example 9: Topical cream

 Dissolve the preservative in warm purified water and allow to cool. Add emulsified wax, mineral oil and white serine and mix well with 70-80. An aqueous solution containing compound 1 is added and stirred. Continue stirring while adding purified water to obtain a topical cream with a total weight of 100 g.

 Per 100g of component

 Compound 1 lOOmg

 15g emulsified wax

 Mineral oil 5g

 5 g of white ヮ serine

 Methyl paraoxybenzoate 200mg

 purified water

 lOOg

Industrial applicability

 INDUSTRIAL APPLICABILITY The present invention has excellent pharmacological activity and is useful as an agent for preventing or treating autoimmune diseases

 'Provide derivatives.

Claims

 The scope of the claims  Formula (I)

(Wherein Ri represents a hydrogen atom, substituted or unsubstituted lower alkyl, lower cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl, R ² , R ³ , R ⁴ and R ⁵ is the same or different and is a hydrogen atom, lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkyl, lower cycloalkanoy Represents substituted or unsubstituted aryloyl, lower alkoxylability, luponyl, cyano, carboxy, halogen, substituted or unsubstituted amino or substituted or unsubstituted carpoxamide, and R ⁶ represents a hydrogen atom, lower alkyl or substituted or unsubstituted represents Ariru substituted, R ⁷ and R ⁸ are taken the same or different hydrogen atom, a lower a Kill, substituted or unsubstituted Ariru, represents lower alkoxy or halogen, R ⁹ represents a substituted or unsubstituted lower alkyl, substituted or unsubstituted § re Ichiru, substituted or unsubstituted a Ararukiru or pyridyl alkyl, A represents lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted pyridyl) or a pharmaceutically acceptable salt thereof. 2. Ri represents a hydrogen atom, R ² , R ³ , R ⁴ and R ⁵ are the same or different and represent a hydrogen atom or a substituted or unsubstituted lower alkoxy, R ⁶ represents a hydrogen atom, R ⁷ and R ⁸ represents a hydrogen atom, R ⁹ represents a substituted or unsubstituted lower alkyl, and A represents a lower alkyl or a substituted or unsubstituted aryl, the benzofuran derivative according to claim 1, or a pharmaceutically acceptable salt thereof. Salt. 3. The benzofuran derivative according to claim 1 or 2, or a pharmacologically acceptable derivative thereof. A medicament comprising an acceptable salt as an active ingredient.  4. A therapeutic agent for an autoimmune disease comprising the benzofuran derivative according to claim 1 or 2 or a pharmacologically acceptable salt thereof as an active ingredient.