WO2006090921A1 - Inhibitory effect of sulfonamide compound on lymphocyte activation - Google Patents

Abstract

A lymphocyte activation inhibitor and a remedy for an autoimmune disease comprising a sulfonamide compound as an active ingredient.

Description

 Inhibition of lymphocyte activation by sulfonamide compounds

Technical field

 The present invention relates to a lymphocyte activation inhibitor. In addition, regarding therapeutic agents for autoimmune diseases, more specifically, therapeutic agents for cellular autoimmune diseases, therapeutic agents for rheumatism, therapeutic agents for multiple sclerosis, therapeutic agents for neuroautoimmune diseases, type I (insulin-dependent) diabetes mellitus Therapeutic agent, Ming

The present invention relates to a therapeutic agent for systemic lupus erythematosus (SLE), a therapeutic agent for inflammatory bowel disease (IBD), and a therapeutic agent for Scherdalen syndrome. Background art

In autoimmune diseases, self-antigen-specific lymphocyte division and activation have been shown to contribute significantly to the worsening of the pathology. That is, autoantigen-specific lymphocytes are activated and proliferated by recognizing a part of the self as a foreign body, and by activating cells of other immune systems, Trigger. Self-antigen lymphocytes with such a mechanism play a very important role in the development of the pathology of autoimmune diseases. Therefore, the progression of autoimmune disease can be suppressed by suppressing the activation of lymphocytes induced by the antigen. Specific examples of autoimmune diseases include cellular autoimmune diseases, rheumatism, multiple sclerosis, neuroautoimmune diseases (eg Guillain-Parée syndrome, neurobehcet's disease), type I (insulin-dependent) diabetes Systemic erythematosus (SLE), inflammatory bowel disease (IBD), Siedalen syndrome, etc. are known as intractable diseases ( ¹⁾ .

Currently, lymphocyte activation inhibitors based on various mechanisms of action are clinically used for the treatment of the above autoimmune diseases. However, although effective, on the other hand, serious side effects can occur, lymphocyte activation inhibitors have not been used frequently, and the development of less toxic lymphocyte activation inhibitors is hoped for. It is rare. By the way, a sulfonamide compound has been reported as a useful antitumor agent.

( ^{2 1-6} ). In particular, N- (3-chloro-1H-indole-7-yl) 4-1sulfamoylbenzenesulfonamide (hereinafter sometimes referred to as “E7070”), N-1 (3_Cyanol-4 —Methyl 1 H—Indole 1—yl) _ 3 _Cyanobene zensulfone amide (hereinafter sometimes referred to as ΓΕ7820), N— [[((4) Black Mole) Amino] Carbonyl] —2, 3 — Dihydro 1 H— ^ f Ndene 1 5 — Sulfonamide (hereinafter sometimes referred to as “LY186641 J”), N-[[((3, 4-jikuguchi mouth Fuenore)) amino] carboni Nole]-2,3—Dihydrobenzofuran 1-sulfone amide (hereinafter sometimes referred to as “LY295501”), N— (2,4-dioctole benzoyl) — 4 1 Honamide (hereinafter sometimes referred to as rLY-ASAPj), N— (2, 4-dichlorobenzoyl) — 5-Promothiophene 2-sulfone amide (hereinafter sometimes referred to as “LY573636”), 2-Sulfanilamide 1-Black mouth quinoxaline (hereinafter sometimes referred to as “CQS”), etc. It is very useful because it shows activity in various types of tumors.

In recent years, it has been reported that E7070 and E7820 force S have an inhibitory effect on lymphocyte activation and are useful as a therapeutic agent for autoimmune diseases ⁽⁷⁾ .

In recent years, methods have been established to detect the expression level of many genes simultaneously using various DNA microarrays, and DNA microarrays have been applied to a wide range of purposes (8 and 9). In addition, several reports have been made on the changes in gene expression that occur when anticancer drugs are applied to tumor cells using DNA microarrays (some of which use membrane filters) ( ¹ ° ^{1). 2)} . These reports show that gene expression variability analysis can be used to comprehensively study the biological changes caused by cells by comparing the characteristics of multiple cell populations and by treating drugs at the molecular level. It is extremely useful.

In addition, by analyzing the gene expression profiles of a panel of 60 cancer cell lines from the US National Cancer Institute, we reclassified these cell lines and examined their characteristics ( ¹³⁾ . Cell line panel gene expression There have been reports ( ¹⁴⁾ that considered the relationship between profiles and susceptibility of each cell line to various anticancer agents.

 References

 (I) Denise LJ, Stephen JG, Noel RR, Neil MHG, Clinical Immunology and Immunopathology, 1997, 84, 223-243.

 (2) Japanese Patent Application Laid-Open No. 7-1 6 5 7 08

 (3) International Publication No. 00Z50 3 9 5 Pamphlet

 (4) European Patent Application Publication No. 0 2 224 7 5

 (5) International Publication No. 02Z09 8 84 No. 8 pamphlet

 (6) International Publication No. 20 0 3Z0 3 5 6 29 Pamphlet

 (7) International Publication No. 0 3/0 2 2 2 7 Panthlet

 (8) Schena M, Shalon D, Davis RW, Brown PO. Science, 1995, 270, 467-70.

 (9) Lockhart, DJ, Dong, H., Byrne, MC, Follettie, MT, Gallo, MV, Chee, MS, Mittmann, M., Wang C, Kobayas i, M., Horton, H. Brown, E 丄., Nature Biotechnology, 1996, 14, 1675-1680.

 (1 0) Rhee CH, Ruan S, Chen S, Chenchik A, Levin VA, Yung AW, Fuller GN, Zhang W, Oncol Rep, 1999, 6, 393-401.

 (I I) Zimmermann J, Erdmann D, Lalande I, Grossenbacher R, Noorani M, Furst P, Oncogene, 2000, 19, 2913-20.

 (1 2) Kudoh K, Ramanna M, Ravatn R, Elkahloun AG, Bittner ML, Meltzer PS, Trent JM, Dalton WS, Chin KV 'Cancer Res, 2000, 4161-6.

 (1 3) Ross DT, Scherf U, Eisen MB, Perou CM, Rees C, Spellman P, Iyer V, Jeffrey SS, Van de Rijn M, Waltham M, Pergamenschikov A, Lee JC, Las kari D, Shalon D, Myers TG, Weinstein JN, Botstein D, Brown PO, Nat Genet, 2000, 24, 227-35.

(1 4) Scherf U, Ross DT, Waltham M, Smith LH, Lee JK, Tanabe L, Kohn KW, Reinhold. WC, Myers TG, Andrews DT, Scudiero DA, Eisen MB, Sausville EA, Pommier Y, Botstein D, Brown PO, Weinstein JN, Nat Genet, 2000, 24, 236-44.

 An object of the present invention is to find a lymphocyte activation inhibitor having an excellent inhibitory effect on lymphocyte activation and an autoimmune disease therapeutic agent based on the inhibitory effect on lymphocyte activation.

 As a result of intensive studies to solve the above-mentioned problems, the present inventors have conducted gene microarray and cancer cell line panel experiments, and found that gene variation caused by E7820, E7070, LY186641, LY295501, LY573636 or CQS or a combination thereof. The pattern and cytostatic activity were found to be highly correlated. In addition, in an assay for measuring cytostatic activity, it was found that the cancer cell lines resistant to E7070, E7820, LY186641, LY295501, LY'ASAP, LY573636, and CQS showed cross resistance. From these results, the present inventor found that E7070, E7820, LY186641, LY295501, LY-ASAP, LY573636 or CQS or a combination thereof has the same or similar mechanism of action, and _the same or similar gene We gained knowledge that it will bring about changes and effects.

 E7070 and E7820 have been reported to have a lymphocyte activation inhibitory effect and are useful as therapeutic agents for autoimmune diseases (WO03 / 022271). Therefore, based on the above findings, sulfonamide compounds, preferably LY186641, LY295501, LY-ASAP, LY573636 or CQS, or a combination thereof, have a lymphocyte activation inhibitory effect and are useful as a therapeutic agent for autoimmune diseases. We found something and came to complete this invention.

 That is, the present invention relates to the following.

 (1) A lymphocyte activation inhibitor comprising a sulfonamide compound as an active ingredient.

 (2) A therapeutic agent for autoimmune diseases comprising a sulfonamide compound as an active ingredient.

(3) Lymphocyte activation characterized by administering sulfonamide compounds to patients Suppression method.

 (4) A method for treating an autoimmune disease, comprising administering a sulfonamide compound to a patient.

 (5) Use of a sulfonamide compound for the production of a lymphocyte activation inhibitor.

(6) Use of a sulfonamide compound for the manufacture of a therapeutic agent for autoimmune diseases. The present invention also relates to the following.

 (7) A kit for treating multiple sclerosis comprising the therapeutic agent according to (2) and a pharmaceutical composition having a nerve cell protecting action.

 (8) A method for treating multiple sclerosis, comprising administering to the patient the therapeutic agent according to (2) and a pharmaceutical composition having a nerve cell protecting action.

 (9) Use of a sulfonamide compound for the production of the kit according to (7). In the above (1) to (9), the sulfonamide compound is

 Formula (I)

[Wherein E represents 1 O—, 1 N (CH ₃ ) 1, 1 CH ₂ —, 1 CH ₂ CH ₂ — or 1 CH ₂ 0—, D represents 1 CH ₂ — or 1 O— And R ^la means a hydrogen atom or a halogen atom, and R ^2a means a halogen atom or a trifluoromethyl group, respectively. ]

 A compound represented by

 General formula (II) '

[Wherein, J represents 1 O— or 1 NH—, Rib represents a hydrogen atom, a halogen atom, an optionally substituted Ci 1 C ₆ alkyl group, or an optionally substituted group. C 1—C4 alkoxy group, optionally substituted d—C ₄ alkylthio group, 1 CF ₃ , —OCF ₃ , 1 SCF ₃ , optionally substituted Ci 1 C ₄ alkoxy Carbonyl group, nitro group, azide group, 1 O (S0 ₂ ) CH ₃ , 1 N (CH ₃ ) 2, hydroxyl group, phenyl group, substituted phenyl group, pyridinyl group, thiyl group, furyl A group, a quinolinyl group or a triazole group, R 1 is a hydrogen atom, a halogen atom, a cyano group, 1 CF ₃ , an optionally substituted d-C ₆ alkyl group, or an optionally substituted group A good C1-C4 alkoxycarbonyl group, an optionally substituted d-C4 alkoxy group, an optionally substituted phenyl group or an optionally substituted quinolinyl group, R Is a hydrogen atom or a d—C ₄ alkoxy group which may have a substituent, R ⁴ b is water Ci 1 C ₆ alkyl group which may have an elementary atom or a substituent (wherein at least one of R 3b and R 4b is a hydrogen atom), R ⁵ b is a hydrogen atom, a halogen atom, a substituent Ci 1 C ₆ alkyl group, which may have a group, 1 CF ₃ or nitro group, R 6b may have a hydrogen atom, a halogen atom or a substituent 1 C ₆ alkyl group (which R ^6b may have a substituent d—C ₆ alkyl group, R ⁵ b is a hydrogen atom, R ^7b is a halogen atom), R ^7b is a halogen atom, good Ci may have a group one C ₆ alkyl group or a CF ₃ (proviso, R ⁵ b or R? one of b is optionally substituted Ci one C ₆ alkyl group der Luke, or R ^7b force S, when a halogen atom or a substituent and may have a d-C ₆ alkyl group, R Others either the R <3b is meant respectively a hydrogen atom). ]

A compound represented by

Formula (III)

A compound represented by

Formula (IV)

And at least one compound selected from the group consisting of the compounds represented by: or a pharmacologically acceptable salt thereof or a solvate thereof. According to the present invention, an excellent inhibitor of lymphocyte activation and a therapeutic agent for Z or autoimmune disease are provided.

 More specifically, a sulfonamide compound exhibiting an excellent inhibitory effect on lymphocyte activation and / or a therapeutic effect on autoimmune diseases, preferably LY186641, LY295501, LY-ASAP, LY573636 or CQS or a combination thereof as an active ingredient. A pharmaceutical composition comprising the above is provided and can be used for the treatment of autoimmune diseases. Also provided is a kit comprising a therapeutic agent for an autoimmune disease containing a sulfonamide compound as an active ingredient and a pharmaceutical composition having a nerve cell protecting action, and is used for the treatment of autoimmune diseases such as multiple sclerosis. It became possible to use it. Brief Description of Drawings

 FIG. 1 shows the results of hierarchical clustering analysis on the DNA microarray in Example 1.

 FIG. 2 shows the correlation coefficient in the DNA microarray in Example 2. FIG. 3 shows the results of hierarchical clustering analysis on the DNA microarray in Example 2.

 FIG. 4 shows the correlation coefficient in the DNA microarray in Example 2. FIG. 5 shows the results of hierarchical clustering analysis on the DNA microarray in Example 2.

Fig. 6 shows HCT116-C9, This shows the growth inhibitory action of E7070, E7820, CQS, LY186641, LY295501 and LY-ASAP against HCT116-C9-C1 and HCT116-C9-C4.

 FIG. 7 shows the growth inhibitory action of E7070 and LY573636 on HCT116-C9, HCT116-C9-C1 and HCT116-C9-C4 in the assay for measuring cytostatic activity. BEST MODE FOR CARRYING OUT THE INVENTION

 Embodiments of the present invention will be described below. The following embodiment is an example for explaining the present invention, and is not intended to limit the present invention only to this embodiment. The present invention can be implemented in various forms without departing from the gist thereof.

 Documents cited in the present specification, as well as patent publications, patent gazettes and other patent documents are incorporated herein by reference.

1. Sulfonamide compounds

 In the present invention, the sulfonamide compound includes a compound represented by the following general formula (I). .

In the above general formula (I), in the formula, E represents 1 O—, 1 N (CH ₃ ) 1, —CH ₂ —, 1 CH ₂ CH ₂ — or 1 CH ₂ 0 1, D represents 1 CH ₂ — or 1 O—, R ^la represents a hydrogen atom or a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, a silicon atom), R ^2a represents a halogen atom or a trifluoromethyl group Each means.

The compound represented by the general formula (I) of the present invention can be produced by a known method. For example, it can be produced by the method described in EP 0222475A1. You can.

 In general formula (I), preferred compounds are LY186641 or LY295501.

LY186641 refers to N-[[((4 chlorophenyl) amino] carbonyl] 1 2 3 -dihydro 1 H-indene 5 -sulfonamide, whose structural formula is shown in the following formula (VII).

 LY186641

 LY186641 can be produced by a known method, for example, by the method described in European Patent Application Publication No. 0222475A1.

 In the present invention, LY295501 refers to N — [[((3,4-dichlorophenyl) amino] canolepo-nore] 1,2,3-dihydrobenzofuran-5-sulphone, The structural formula is shown in the following formula (VIII).

 LY295501

 LY295501 can be produced by a known method. For example, LY295501 can be produced by the method described in European Patent Application Publication No. 0222475A1 / "or European Patent Application Publication No. 0555036A2.

 In the present invention, the sulfonamide compound includes a compound represented by the following general formula (II). '

In the general formula (II), J is 1 O— or 1 NH—, R ib is a hydrogen atom, a halogen atom, or a d-C ₆ alkyl group which may have a substituent, a substituent The D-C alkoxy group which may have, Ci 1 C ₄ alkylthio group which may have a substituent, 1 CF ₃ , 1 OCF ₃ , 1 S CF ₃ , which may have a substituent Good Ci 1 C4 alkoxycarbonyl group, nitro group, azide group, 1 O (S0 ₂ ) CH ₃ , 1 N (CH ₃ ) 2, hydroxyl group, phenyl group, substituted phenyl group, pyridinyl group, chenyl group , A furyl group, a quinolinyl group or a triazole group, R ² ¾ represents a hydrogen atom, a halogen atom, a cyan group, one CF ₃ , an optionally substituted Ci 1 C ₆ alkyl group, or a substituent. D-C ₄ alkoxycarbo group which may have, Ci-C ₄ alkoxy group which may have a substituent, phenyl group which may have a substituent or a substituent. the good quinolinyl group optionally, R ^3b is a hydrogen atom or may have a location substituent Ci one C4 The alkoxy group, R ^4b is, which may have a hydrogen atom or a substituent d-C ₆ alkyl group (provided that at least one of R ³ b and R ⁴ b is hydrogen atom), R ⁵ b is a hydrogen atom, a halogen atom, an optionally substituted Ci 1 C ₆ alkyl group, 1 CF ₃ or a nitro group, R 6b is a hydrogen atom, a halogen atom or a substituent. Ci—C ₆ alkyl group (where R ⁶ b is optionally substituted Ci 1 C ₆ alkyl group, R ⁵ b is a hydrogen atom, R ⁷ b is a halogen atom) R ⁷ b is a halogen atom, which may have a substituent Ci 1 C ₆ alkyl group or one CF ₃ ( ^wherein either R ^5¾ or R ^7b has a substituent) D—C ₆ alkyl group, or R ₆ -b may have a halogen atom or a substituent d— In the case of a C ₆ alkyl group, each of R ⁵ b and R ⁶ b is a hydrogen atom).

 In the general formula (Π), the “halogen atom” is preferably a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. '

In the general formula (Π), “C 1 C ₆ alkyl group” means a straight chain or branched alkyl group having 1 to 6 carbon atoms, and is not particularly limited, Methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentinole group (amyl group), isopentyl group, neopentyl group, tert —Pentyl group, 1-methylbutyl group, 2-methyl group Tylptyl group, 1,2-dimethylpropyl group, n-hexyl group, isohexyl group, 1-methylpentyl group, 2-methylenopentyl group, 3-methylpentyl group, 1-ethylpropyl group, 1,1-dimethylbutyl group, 1, 2 —Dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethyl / rebutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1, It means 1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, etc. Among these, preferred groups are methyl group, ethyl group, n-propyl group, isopropylinole group, n-butyl group, isobutynole group, sec-butynole group, tert-butyl group, n-pentyl group, n- A hexyl group etc. can be mentioned.

 —In the general formula (II), “d—C 4 alkoxy group” means an alkoxy group having 1 to 4 carbon atoms, and is not particularly limited, but preferably a methoxy group, an ethoxy group N-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-ptoxy group and the like.

— In the general formula (II), in the “Ci 1 C ₄ alkylthio group”, the alkyl group is not particularly limited, but methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl Tert-butyl and the like. In the general formula (II), examples of the “d—C 4 alkoxycarbonyl group” are not particularly limited, but include a methoxycarbonyl group, an ethoxyquincarbonyl group, an n-propoxycarbonyl group, an isopropoxy group, and the like. Examples thereof include a carboninole group, an n-butyloxycarbonyl group, an isoptoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarol group, and the like.

In the general formula (II), examples of the substituent to be introduced, is not particularly limited, for example, C i_ C ₆ alkyl group (e.g., methyl group, Echiru group, n- propyl group, an isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-pentyl group, etc.), d-C ₄ alkoxy group (eg, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, Isobutoxy group, sec-butoxy group, tert-butoxy group, etc.), amino group, hydroxyl group, halogen atom (for example, A fluorine atom, a chlorine atom, a bromine atom, an iodine atom) or a substituent such as a silyl group. '

 The compound represented by the general formula (II) of the present invention can be produced by a known method, for example, by the method described in WO 02/098848 pamphlet (WO02 / 098848).

 In the general formula (Π), a preferred compound is LY-ASAP.

LY-ASAP refers to N— (2,4-dichlorobenzoic) 14-cyclophenyl sulfonamide, and its structural formula is shown in the following formula (XI).

 LY-ASAP

 LY-ASAP can be produced by a known method, for example, by the method described in International Publication No. 02 09884 8 pamphlet (WO02 / 098848).

 In the present invention, examples of the sulfonamide compound include LY573636. In the present invention, LY573636 refers to N- (2,4-diethyl benzoyl) 15-bromothiophene-2-sulfonamide, and the structural formula thereof is shown in the following formula (III).

 LY573636

 LY573636 is preferably a sodium salt.

 LY573636 can be produced by a known method. For example, in the same manner as described in International Publication No. 02/09884 Panflet (WO02 / 098848), commercially available 5-bu-mochiophene mono-2-sulfo-luculide and It can be produced from 2,4-dichlorobenzoic acid.

In addition, LY573636 is published in International Publication No. 2003/035629. (WO2003 / 035629) can be produced by the method described in Example 63. In the present invention, examples of the sulfonamide compound include CQS. In the present invention, CQS refers to 2-sulfanilamide 5-clomouth quinoxaline, the structural formula of which is shown in the following formula (IV).

 CQS can be produced by a known method, for example, by the method of (J. Am. Chem. Soc, 1947, 71, 6 · 10). Sulfonamide compounds may form pharmacologically acceptable salts with acids or bases. The sulfonamide compound in the present invention includes these pharmacologically acceptable salts. Examples of salts with acids include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, and phosphate, formic acid, acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citrate, tartaric acid, Mention may be made of salts with organic acids such as benzoic acid, methanesulfonic acid, benzenesulfonic acid, ρ-toluenesulfonic acid, trifluoroacetic acid. In addition, as a salt with a base, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, trimethylamine, triethylamine, pyridine, picoline, dihexylhexylamine, Ν ,

Examples thereof include salts with organic bases such as N′-dibenzylethylenediamine, arginine, and lysine (organic amine salts) and ammonium salts.

 The sulfonamide compound may be an anhydride or may form a solvate such as a hydrate. The solvate may be either a hydrate or a non-hydrate, but a hydrate is preferred. As the solvent, water, alcohol (for example, methanol, ethanol, η-propanol), dimethylformamide, or the like can be used.

In addition, when solvates and / or optical isomers of these compounds exist, The sulfonamide compounds in the present invention include those solvates and / or optical isomers. In addition, the sulfonamide compound in the present invention includes a sulfonamide compound that undergoes metabolism such as oxidation, reduction, hydrolysis, and conjugation in vivo. Furthermore, the sulfonamide compound in the present invention also includes a compound that generates a sulfonamide compound by being subjected to metabolism such as oxidation, reduction, and hydrolysis in vivo.

2. Pharmaceutical composition, kit, method for inhibiting lymphocyte activation, method for treating autoimmune disease The present invention relates to a pharmaceutical composition kit containing a sulfonamide compound as an active ingredient, and lymphocyte activation using these. The present invention relates to a method for suppressing and treating autoimmune diseases.

 In the present invention, the sulfonamide compound is as described in “1. Sulfonamide Compound”. For example, from the general formula (I), the general formula (Π), the formula (III), and the formula (IV), At least one compound selected from the group consisting of, preferably at least one compound selected from the group consisting of LY186641, LY295501, LY'ASAP, LY573636 and CQS, more preferably selected from the group consisting of LY295501 and LY573636 At least one compound, particularly preferably the sodium salt of LY573636.

 In the present invention, the sulfonamide compound includes pharmacologically acceptable salts or solvates such as hydrates thereof.

 The lymphocyte activation inhibitor and the therapeutic agent for no- or autoimmune diseases of the present invention are pharmaceutical compositions comprising a sulfonamide compound as an active ingredient.

 The inhibitor of lymphocyte activation and the therapeutic agent for autoimmune disease of the present invention are useful as a lymphocyte activation inhibitor and Z or autoimmune disease therapeutic agent.

 In the present invention, the lymphocyte activation inhibitor is a pharmaceutical composition having an action of reducing the activity of lymphocytes, an action of suppressing activation of lymphocytes, or an action of suppressing the rate of increase in lymphocyte activity.

In the present invention, the treatment is to alleviate the symptoms of the disease and suppress the progression of the disease symptoms. Control, removing disease symptoms, improving disease prognosis, and preventing disease. The effect of treatment can be confirmed by biochemical examination, pathological diagnosis, and the like.

 In the present invention, the autoimmune disease is not particularly limited. For example, cellular autoimmune disease, rheumatism, multiple sclerosis, neuroautoimmune disease (Guillain-Barre syndrome, neuro-Behcet's disease, etc.), type I (insulin-dependent type) And at least one selected from the group consisting of diabetes, systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) and Sigren's syndrome.

 The lymphocyte activation inhibitor and the z or autoimmune disease therapeutic agent of the present invention are used for mammals (eg, humans, rats, rabbits, hidges, pigs, sushi, cats, dogs, monkeys, etc.). Can be administered.

 A kit for treating an autoimmune disease of the present invention, preferably multiple sclerosis, comprises a pharmaceutical composition comprising a sulfonamide compound as an active ingredient (for example, a therapeutic agent for self-immune disease), and nerve cells. A kit comprising a pharmaceutical composition having a protective action and a combination thereof.

 The kit of the present invention is useful as a kit for treating an autoimmune disease, preferably multiple sclerosis. _

 The nerve cell protective action means an action of suppressing pathological changes such as nerve axonal degeneration in autoimmune diseases such as multiple sclerosis by directly acting on nerve cells. Examples of pharmaceutical compositions having a nerve cell protecting action include glutamate antagonists, sodium channel antagonists, calcium channel antagonists, dopamine antagonists, monoamine oxidase B inhibitors and the like. There are no particular limitations on the dosage form of the pharmaceutical composition having neuronal cell protective activity contained in the kit.

 Examples of glutamate antagonists include topiramate. Topiramate can be produced by a known method, or can be obtained by purchasing a commercial product.

Sodium channel antagonists include, for example, apuridine, quinidine, disovillamide, dibenzoline, flecainide, pilsicainide, pro-force inamide, Propafenone, mexiletine, lidocaine and the like. The sodium channel antagonist can be produced by a known method, or can be obtained by purchasing a commercially available product.

 Calcium channel antagonists include, Examples include verano minole, funorenalidine, and cinnarizine. The calcium channel antagonist can be produced by a publicly known method, and can be obtained by purchasing a commercial product.

 Dopamine antagonists include, Can be mentioned. Dopamine antagonist can be produced by a known method, and can be obtained by purchasing a commercial product.

 Examples of monoamine oxidase B inhibitors include selegiline. Selegiline can be produced by a known method, or can be obtained by purchasing a commercial product.

 A substance having a nerve cell protecting action contained as an active ingredient of a pharmaceutical composition having a nerve cell protecting action may form a pharmacologically acceptable salt with an acid or a base. In addition, the substance having a nerve cell protecting action may be an anhydride or a solvate. Further, it may be an optical isomer, a substance that undergoes metabolism in vivo, or a substance that is produced by metabolism. Examples of pharmacologically acceptable salts, solvates, isomers, metabolized substances, and metabolized substances are as described in “1. Sulfonamide Compounds”.

The kit for the treatment of autoimmune disease of the present invention, preferably multiple sclerosis, can be applied to mammals (eg, humans, rats, rabbits, hidges, puta, sushi, cats, nu, monkeys, etc.). On the other hand, it can be used.

 In the present invention, “combined” means a combination for using compounds in combination, and includes both forms in which separate pharmaceutical compositions are used together at the time of administration, and forms as a mixture.

 In the kit for the treatment of autoimmune disease of the present invention, preferably multiple sclerosis, a pharmaceutical composition comprising a sulfonamide compound as an active ingredient and a pharmaceutical composition having a nerve cell protecting action are mixed. Or may be stored separately and packaged together, or may be administered simultaneously, or one of them may be administered first.

 The kit for the treatment of autoimmune disease of the present invention, preferably multiple sclerosis, includes a pharmaceutical composition comprising a sulfonamide compound as an active ingredient and a pharmaceutical composition having a nerve cell protecting action, a packaging container, It may contain instruction manuals and attached documents. Packaging containers, instruction manuals, package inserts, etc. can describe combinations for the combined use of compounds, and forms or mixtures as separate pharmaceutical compositions are used at the time of administration The usage, dose, etc. can be described. Usage and dosage can be described with reference to the following.

 When the lymphocyte activation inhibitor, the autoimmune disease therapeutic agent, or the autoimmune disease treatment kit such as multiple sclerosis of the present invention is used, it can be administered orally or parenterally.

 When using the lymphocyte activation inhibitor of the present invention, an autoimmune disease therapeutic agent, or an autoimmune disease treatment kit such as multiple sclerosis, the dosage of the sulfonamide compound depends on the degree of symptoms, It depends on the patient's age, gender, body weight, sensitivity difference, administration method, administration time, administration interval, nature of pharmaceutical preparation, preparation, type, type of active ingredient, etc., and is not particularly limited, but normal adult (body weight 6 O Kg ) 10 to 6000 mg per day, preferably 50 to 4000 mg, more preferably 50 to 2000 mg.

Can be administered in 3 divided doses.

When using the kit for the treatment of autoimmune disease of the present invention, preferably multiple sclerosis, the dose of the substance having a nerve cell protective action is the degree of symptoms, patient age, sex, body Weight, sensitivity difference, administration method, administration timing, administration interval, nature of pharmaceutical preparation, preparation, type, type of active ingredient, etc., but not particularly limited, but normal adult (body weight 60 Kg) 10-6000 per day mg, preferably 50 to 4000 mg, more preferably 50 to 2000 m, which can be administered usually in 1 to 3 divided doses per day. The lymphocyte activation inhibitor and / or autoimmune disease therapeutic agent of the present invention can be prepared in various dosage forms, for example, oral solid preparations, or parenteral preparations such as injections, suppositories, ointments, and poultices. And so on.

 In addition, the pharmaceutical thread and composition contained in the kit for the treatment of autoimmune disease of the present invention, preferably multiple sclerosis, as long as it contains a sulfonamide compound or a substance having a nerve cell protective action as an active ingredient The shape is not particularly limited. The compound or substance can be made into various dosage forms, for example, oral solid preparations or parenteral preparations such as injections, suppositories, ointments and cataplasms.

 When preparing a solid preparation for oral administration, add excipients, and if necessary, binders, disintegrants, lubricants, coloring agents, flavoring agents, etc. to the active ingredient. Covered tablets, granules, fine granules, powders, capsules, etc. Oral non-solid preparations such as dip can also be prepared as appropriate.

 Examples of excipients include lactose, corn starch, sucrose, glucose, sorbite, crystalline cellulose, and silicon dioxide. Examples of binders include polybuenorenoreconole, ethinoresenorelose, and methinoresenorelose. Gum Arabic, Hydroxypropyl Cellulose, Hydroxyl Pill Methyl Cellulose, etc. Lubricants such as magnesium stearate, talc, silica, etc. are permitted to be added to pharmaceuticals as colorants. However, as a flavoring agent, for example, cocoa powder, heartbeat brain, aromatic acid, heart force oil, dragon brain, cinnamon powder and the like are used. Of course, these tablets and granules may be appropriately coated with sugar coating, gelatin coating, etc. if necessary.

When preparing injections, add pH adjusters, buffers, suspending agents, solubilizing agents, solubilizers, tonicity agents, preservatives, etc. to the active ingredient as necessary. Subcutaneous, intramuscular injection, and intravenous infusion. At that time, if necessary, by conventional methods It can also be a lyophilized product.

 Examples of the suspending agent include methylcellulose, polysorbate 80, hydroxichetinoresenololose, gum arabic, tragacanth powder, canoleboxymethinorescenole mouth sodium, polyoxyethylene sorbitan monolaurate, etc. You can.

 Examples of the solubilizer include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, macrogol, and castor oil fatty acid ethyl ester.

 Examples of the stabilizer include sodium sulfite and sodium metasulfite, and examples of the preservative include methyl paraoxybenzoate, ethyl parabenzoate, sorbic acid, phenol, cresonole, and black mouth crezo monore. be able to.

 The present invention also includes the use of a sulfonamide compound for the manufacture of a lymphocyte activation inhibitor, an autoimmune disease therapeutic agent, or a kit for the treatment of autoimmune disease, preferably multiple sclerosis.

 Furthermore, the present invention includes a method for inhibiting lymphocyte activation or a method for treating autoimmune disease, wherein a pharmaceutical composition containing a sulfonamide compound as an active ingredient is administered to a patient.

 The present invention also provides a patient with a pharmaceutical composition containing a sulfonamide compound (for example, a therapeutic agent for an autoimmune disease containing the compound as an active ingredient) and a pharmaceutical composition having a nerve cell protecting action. This includes treatment methods for autoimmune diseases such as multiple sclerosis.

Administration of a pharmaceutical composition containing a sulfonamide compound or a pharmaceutical composition having a neuronal cell protective action in the method for inhibiting lymphocyte activation, the method for treating an autoimmune disease, or the method for treating multiple sclerosis according to the present invention. The route and administration method are not particularly limited, but the description of the inhibitor, therapeutic agent or kit can be referred to. Hereinafter, the present invention will be described with specific examples, but the present invention is not limited thereto. There is no. Example 1 DNA microarray analysis

 (1) Cell culture, compound treatment, and RNA extraction

For the purpose of examining gene expression changes induced by compounds by DNA microarray analysis, human colon cancer-derived cell line HCT116 (American IVpe Culture Collection, Manassas, VA, USA) and human leukemia-derived cell line MOLT-4 ( American Type Culture Collection, Manassas, VA, USA) was cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 units / ml penicillin, 100 μg / ml streptomycin. Thereafter, the culture and compound treatment were performed in an incubator adjusted to 5% C02 and 37 ° C. HCT116 cells and MOLT-4 cells were seeded at a rate of 2.0 × 10 ⁶ cells / dish in a 10 cm diameter cell culture dish, and the following compound treatment was performed after 24 hours of culture.

For HCT116 cells, E7820 (0.8 μΜ), Ε7070 (0.8 μM), LY295501 (30 μΜ), CQS (8 μΜ), adriamycin (0.2 μΜ), daunomycin (0.2 Μ), ICRF154 (80 μ μ) 12 compounds, i.e., ICRF159 (80 μΜ), kenpaullone (10 μΜ), alsterpullone (10 μΜ), trichostatin Α (0.1 μΜ), and rapamycin (80 / Μ) were evaluated. On the other hand, for MOLT-4 cells, Ε7070 (0.8 μΜ) was evaluated. Here, adriamycin and daunomycin are DNA topoisomerase II inhibitors that interfer with DNA, ICRF154 and ICRF159 are catalytic type DNA topoisomerase II inhibitors (J ヽ kenpaullone and alsterpullone are cyciin-dependent kinases (CDKs) inhibitor, trichostatin A is nistone deacetylase | ¾. Harmful agent, rapamycin 'is a known compound as mTOR / FRAP inhibitor, respectively. Based on the 50% growth inhibition concentration for HCT116 cells (based on the 3-day cytostatic activity using WST-8), the concentration was set to 3 to 5 times that shown in parentheses following the above compound name. Cells were collected after treatment at the set concentration for 24 hours, and cells cultured for 24 hours without addition of compounds were also collected. Total UNA was extracted from the collected cells using TRIZOL reagent (manufactured by Invitrogen) according to the attached operation method.

 (2) Gene expression analysis by DNA microarray

The resulting RNA is dissolved in 100 il of diethylpyrocarbonate (DEPC) -sterilized water and further purified using an RNeasy column (QIAGEN), Superscript Choice System (Invitrogen) and T7'd (T ) Double-stranded cDNA was synthesized using ₂₄ primers.

First, add 5 M T7-d (T) ₂₄ primer, lx First strand buffer, 10 mM DTT, 500 μΜ dNTP mix, and 20 units / μΐ Superscript II Reverse Transcriptase to 10 // g RNA. The reaction was carried out at 42 ° C for 1 hour to synthesize single-stranded DNA. Then add lx Second strand buffer, 200 μM dNTP mix, 67 U / ml DNA ligase, 270 U / ml DNA polymerase I, and 13 U / ml RNase H, 2 at 16 ° C. Double-stranded cDNA was synthesized by reacting for a period of time. Further, 67 U / ml T4 DNA polymerase I was added and reacted at 16 ° C for 5 minutes, and then 10 zl of 0.5 M EDTA was added to stop the reaction.

 The obtained cDNA was purified with phenol / chloroform, and labeled with biotinylated UTP and CTP using UNA Transcript Labeling Kit (Enzo Diagnostics) according to the attached operation method. The reaction product was purified with an RNeasy column, and then cRNA was fragmented by heating at 94 ° C for 35 minutes in 200 mM trisacetic acid pH8.1, 150 mM magnesium acetate, 50 mM acetic acid.

The fragmented cRNA was hybridized to GeneChip (Affymetrix) Human Focus array in 100 mM MES, 1 M sodium salt, 20 mM EDTA, 0.01% Tween 20 at 45 ° C. for 16 hours. Hi: After re-generation, GeneChip was washed and stained according to the protocol Midi-euk2 attached to the Affymetrix fluidics station. For the staining, streptavidin-phycoerythrin and piotinylated anti-streptavidin antibody were used. The stained GeneChip was scanned using an HP argon ion laser confocal microscope (Hewlett Packard), and the fluorescence intensity was measured. The measurement is performed at a wavelength of 488 nm and at a wavelength of 570 nm. I went with emission.

 All quantitative data analysis was performed using GeneChip software (Affymetrix) and Gene Spring (Silicongenetics). When using GeneChip software ^ to evaluate gene expression changes due to compounds, the RNA quantification value is dissociated more than twice between the two conditions of the compound-treated group and the untreated group. It was judged that gene expression was significantly “increased” or “decreased”. When evaluating the similarity of gene expression changes induced by each compound using Gene Spring, hierarchical clustering analysis was performed based on the expression changes of all genes on the Human Focus Array.

 The results of hierarchical clustering analysis of HCT116 cells are shown in FIG.

 As a result of angular analysis, adriamycin and daunomycin, ICRF154 and ICRF159, KenpauUone and alsterpullone, which have the same mechanism of action, each caused similar genetic changes (Fig. 1). Therefore, it was confirmed that compounds having the same mechanism of action cause similar genetic changes.

 E7070, E7820, LY295501 and CQS caused similar genetic changes (Figure 1). Therefore, this analysis strongly suggests that E7070, E7820, LY295501 and CQS have the same or similar mechanism of action and bring about the same or similar genetic alterations and effects. Example 2 DNA microarray analysis

HCT116 cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 units / ml penicillin, 100 g / ml streptomycin. The culture and compound treatment were performed in an incubator adjusted to 5% CO ₂ and 37 ° C. HCT116 cells were seeded in a 10 cm diameter cell culture dish at a ratio of 2.0 × 10 ⁶ cells Z dish, and the following compound treatment was performed after 24 hours of culture.

In this example, using HCT116 cells, E7820 (0.16 ^ Μ), Ε7070 (0.26 Μ), LY186641 (59 M), LY295501 (24 μΜ), LY573636 (9.6 μΜ), CQS (4.0 μΜ), MST16 (Ιθθ Μ) etoposide (3.6 μ Μ), ethoxzolamide (410 μ Μ), capsaicin 4195

Changes in gene expression when treated with 12 compounds (28θ ί Μ), trichostatin A (0.16 _ί Μ), and kenpaullone (7.1 M) were examined.

 Here, MST16 is a catalytic type of DNA topoisomerase II inhibitor, and etoposide is responsible for the formation of a cleavable complex. ], Ethoxzolamide is a carbonic anhydrase inhibitor (J, capsaicin is a tumor-specific plasma membrane NADH oxidase inhibitor [|, trichostatin A is histone deacetylase inhibitor U, kenpaullone is a cyclin-dependent kinases (CDKs) inhibitor: ^ lj Each is a known compound.

 The compound treatment concentration was set to twice the concentration based on the 50% growth inhibitory concentration of each compound on HCT116 cells (based on the 3-day cytostatic activity using MTT). Cells were collected after treatment for 24 hours at the set concentration indicated in parentheses following the compound name. Similarly, cells cultured for 24 hours without the addition of the compound were also collected.

 Extraction of total RNA from the collected cells was performed using TRIZOL reagent (manufactured by Invitrogen) according to the attached operation method.

 Gene expression analysis using a DNA microarray was performed in the same manner as “(2) Gene expression analysis using DNA microarray” in Example 1.

In addition, this example was performed in duplicate for each sample (for convenience of experiments, branch numbers were assigned in the manner of control-1, control-2, E7820_l, and E7820-2 so that each sample could be distinguished. ) Then, gene expression change induced by each compound was analyzed using Gene Chip (Affymetri) system (Human Focus array). Of the 26 samples (13 samples X2 of control + 12 compounds) obtained in this example, “.cel” fa / recos, J ”and Ri method (.robust muiti” arrav average method (Biostatistics (2003), 4 , 249-264)), and after normalizing at the probe level, the log value of the signal intensity at the gene level was calculated. Next, subtract the log value of the signal intensity in the compound-untreated group (control-1) from the log value of the signal intensity in the compound-treated group for each gene to obtain the log value of the signal ratio of the compound-treated group to control-l. Obtained. The cosine correlation coefficient was calculated and used as the correlation coefficient between experiments (Fig. 2). This Using the UPGMA method (Unweighted Pair Group Method with Arithmetic mean method) ', a similar clustering analysis was performed (Fig. 3). The same calculation was performed for ₀ control-2 (Fig. 4 and Figure 5). The software used was R 2.0.l (httpV / www.r-project.org /) and affy package 1.5.8 (http://www.bioconductor.org).

 2 to 5, “LY1” is LY186641, “: LY2” is LY295501, “: LY5J is LY573636,“ CAI ”is ethoxzolamide,“ Cap ”is capsaicin,“ MST ”is MST16, “Etop” indicates etoposide, “TSA” indicates trichostatin A, and “Kenp” indicates kenpaullone. In Fig. 3 and Fig. 5, "de hclust (*," average ")" is a command used for statistical analysis, and clustering analysis by R is performed using the average value of dupulicate experimental data. Indicates that it has been done.

 As a result of analysis, the gene changes caused by E7070, E7820, LY186641, LY295501, LY573636 and CQS, HCT116 cells showed very high similarity, and any other compound (MST16, etoposide, ethoxzolamide, capsaicin, trichostatin A and kenpaullone) were also found to be different (Figs. 2 to 5). Therefore, this analysis strongly suggests that E7070, E7820, LY186641, LY295501, LY573636, and CQS are considered to have the same or similar mechanism of action and bring about the same or similar genetic changes and effects. Example 3 Cancer Cell Line Panel Experiment

Using a panel of 36 human cancer cells, the correlation of the cell growth inhibitory activity of E7820, E7070, CQS, LY186641, and LY295501 was examined. The cancer cell lines used were DLD-1, HCT15, HCT116, HT29, SW480, SW620, WiDr (above human colon cancer cell line), A427, A549, LX-1, NCI-H460, NCI-H522, PC -9, PC-10 (above human lung cancer cell lines), GT3TKB, HGC27, MKNl, MKN7, MKN28, MKN74 (above human gastric cancer cell lines), AsPC-1, KP-1, KP-4, MiaPaCall , PANC-1, SUIT-2 (above, human cancer cell line), BSY-1, HBC5, MCF-7, MDA-MB-231, MDA-MB-435, MDA-MB- 468 (above, human breast cancer cell line), CCRF-CEM, HL60, K562, MOLT-4 (above, human leukemia cell line), 6 types, all cells are 10% fetal bovine serum, 100 units The cells were cultured in RPMI-1640 medium supplemented with / ml penicillin and 100 μg / ml streptomycin at 37 ° C. under 5% CO ₂ conditions (Table 1).

table 1

36 human cancer cell lines tested m 3-dav MTT assays

Colon Stomach Breast

 DLD-1 (1250 / welI, 16.8 h) GT3TKB (2000 / well, 21.1 h) BSY-l (2000 / well, 46.1 h)

 HCT15 (1500 / well, 14.5 h) HGC27 (1500 / well, 14.6 h) HBC5 (2000 / well, 31.8 h)

 HCT116 (1250 / well, 13.4 h) MKN1 (4000 / well, 35.9 h) MCF-7 (3000 / weII, 29.5 h) HT29 (2500 / well, 19.8 h) MKN7 (3000 / weII, 37.4 h) MDA-MB231 (2000 / well, 21.6 h) SW480 (3000 / weIl, 19.5 h) MKN28 (2000 / well, 22.7 h) MDA-MB-435 (3000 / well, 24.4 h) SW620 (2500 / well, 17.3 h) MK 74 (4000 / well, 24.8 h) MDA-MB-468 (3000 / well, 34.2 h) WiDr (2000 / weIl, 18.9 h)

 Pancreas leukemia

 Lung AsPC-1 (2500 / well, 28.4 h) CCRF-CEM (1500 / well, 27.2 h)

A427 (2500 / well, 32.4 h) KP-1 (2000 / well, 24.8 h) HL60 (1500 / well, 29.5 h)

 A549 (1250 / well, 18.9 h) KP-4 (2000 / well, 16.7 h) K562 (1500 / well, 20.6 h)

 LX-1 (2000 / well, 17.2 h) MiaPaCall (2500 / well, 19.1 h) MOLT-4 (1500 / well, 22.3 h) NCI-H460 (1000 / well, 13.6 h) PANC-1 (2500 / well, 27.9 h)

 NCI-H522 (4000 / well, 80.4 h) SUIT-2 (2000 / well, 15.6 h)

 PC-9 (2000 / well, 23.7 h)

 PC-10 (2000 / well, 24.0 h)

Cell line (initial cell number, doubling time)

Table 1 shows the types of human cancer cell lines, the number of cells and the doubling time in human cancer cell line panels.

The number of cells listed in Table 1 was added to a 96-well microplate (flat bottom) (50 1 / well), and a compound of a 3-fold dilution series was added 24 hours later (50 μ1Λνβ11). Further 72 hours later, WST-8 (10 μ 1 / well) was added, and the absorbance at 450 nm was measured. The 50% growth inhibitory inhibitory concentration for all 36 cancer cells was determined by the least square method, and the patterns were compared among the compounds. As a correlation index, we used Pearson's correlation coefficients (Paull, KD et al. Display and analysis oi patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm.J. Natl. Cancer Inst. 1989, 81, 1088- 1092; Monks, A. et al. Feasibility of a high-flux anticancer drug screen using a. A diverse panel of cultured human tumor cell lines. J. Natl. Cancer Inst. 1991, 83, 757-766.).

 As a result, E7070, E7820, LY186641, LY295501 and CQS showed a high correlation coefficient in the growth inhibitory activity against each cancer cell line (Table 2). Therefore, this analysis strongly suggests that E7070, E7820, LY186641, LY295501 and CQS have the same or similar mechanism of action, and bring about the same or similar gene change effect. Table 2

 E7070 E7820 CQS LY186641 LY295501

 E7070 1.00 0.98 0.97 0.93 0.80

 E7820 0.98 1.00 0.96 0.95 0.82

 CQS 0.97 0.96 1.00 0.92 0.82

 LY186641 0.93 0.95 0.92 1.00 0.81

 LY295501 0.80 0.82 0.82 0.81 1.00

 Table 2 shows the correlation coefficients between compounds (E7070, E7820, CQS, LY186641 and LY295501) in a human cancer cell line panel. Example 4 Cross resistance in E7070 resistant strains

 The cell growth inhibitory activity of E7820, LY186641, LY295501, LY-ASAP and CQS was evaluated using E7070 resistant strains. HCT116-C9 is a sub-strain isolated from human colorectal cancer-derived HCT116 (American Type Culture Collection, Manassas, VA, USA) .HCT116-C9 is cultured in the presence of E7070, and the E7070 concentration is gradually increased. The E7070 resistant substrains obtained by raising are HCT116-C9-C1 and HCT116-C9-C4 (Molecular Cancer Therapeutics, 2002, 1, 275-286).

Three cell lines HCT116-C9, HCT116-C9-C1, and HCT116-C9-C4 were spread at 3000 cells / well on a 96-well microphone mouthplate (flat bottom) (50 zl / well) and diluted 3 times after 24 hours. A series of compounds was added (50 μ1Ανβ11). In addition, after 72 hours Cell growth inhibitory activity was evaluated by the MTT method (Mossinann IV, J. Immunol. Methods, 1983, 65, 55-63). The 50% growth inhibitory inhibitory concentration for each cancer cell was determined by the least square method.

 As a result, the cytostatic activity of E7070 was 0.127 M with respect to HCT116-C9 (C9). In contrast, the activity against HCT116-C9-C1 (C9C1) and HCT116-C9-C4 (C9C4) is IC50 = 31.9 μΜ and 26.9 μΜ, respectively, and the cell growth inhibitory activity of Ε7070 against C9C1 and C9C4 is remarkable. (Fig. 6). In addition, for E7820, CQS, LY186641, LY295501, and LY-ASAP, the activity against HCT116-C9 was IC50 = 0.080 Μ, 1 · 73μΜ, 33.6μΜ, 10.9Μ, and 1.63μΜ, respectively. In contrast, the activity against HCT116-C9-C1 and HCT116-C9-C4 is IC50 = 51.2 for HCT116-C9-C1, respectively, Μ, 634 / ζΜ, 134 / Μ, 111μΜ, 113 ^ 113 HCT116-C9-C4 were IC50 = 52 · 8; ζ Μ, 517 / ζΜ, 138 / ζΜ, 110 // Μ, 90.3, respectively. Therefore, the cell growth inhibitory activity of Ε7820, CQS, LY186641, LY295501, and LY-ASAP was significantly reduced in the activity against C9C1 and C9C4 compared to the activity against C9 (FIG. 6). Therefore, E7070, E7820, LY186641, LY295501, LY-ASAP and CQS are considered to have the same or similar mechanism of action, strongly suggesting that they produce the same or similar genetic changes and effects. Example 5 Cross resistance in E7070 resistant strains

 In exactly the same manner as in Example 4, the cell growth inhibitory activity of LY573636 was evaluated simultaneously with E7070 using an E7070 resistant strain.

As a result, the cytostatic activity of E7070 was significantly higher than that of HCT116-C9 (IC50 = 0.127 μΜ) and HCT116-C9-C1 and HCT116-C9-C4 (IC50 = 32.7 μΜ and 28.0 μΜ, respectively). Again, it was confirmed that it decreased (Fig. 7). In addition, the cytostatic activity of LY573636 was higher than that of HCT116-C9 (IC50 = 5.11 ^ M), compared with that of HCT116-C9-C1 and HCT116-C9-C4. Activity (IC50 = 264 Μ and 240 μΜ, respectively) was significantly reduced (Fig. 7). Therefore, LY573636 was considered to have the same or similar mechanism of action as Ε7070, and strongly suggested that LY573636 produces the same or similar genetic changes and effects.

 These results (Examples 1 to 5) force, ら 7070, Ε7820, LY186641, LY295501, LY-ASAP, LY573636 or CQS or their combination force The same or similar genetic change and the same or similar action and effect It became clear that it would bring about.

 Therefore, as in Ε7070 and Ε7820 (WO03 / 022271), a sulfonamide compound, preferably LY186641, LY295501, LY_ASAP, LY573636 or CQS, or a combination thereof has a lymphocyte activation inhibitory action, and is a therapeutic agent for autoimmune diseases. It became clear that it was useful as. Industrial applicability

 According to the present invention, an excellent inhibitor of lymphocyte activation and a therapeutic agent for neuro- or autoimmune disease are provided.

 More specifically, sulfonamide compounds exhibiting excellent lymphocyte activation-inhibiting action and therapeutic effects on Z or autoimmune diseases, preferably LY186641, LY295501, LY-ASAP, LY573636 or CQS or a combination thereof is effective. A pharmaceutical composition containing it as an ingredient has been provided and can be used for the treatment of autoimmune diseases. Also provided is a kit comprising a therapeutic agent for an autoimmune disease containing a sulfonamide compound as an active ingredient and a pharmaceutical composition having a nerve cell protecting action, and is used for the treatment of autoimmune diseases such as multiple sclerosis. It became possible to use.

Claims

 The scope of the claims

1. A lymphocyte activation inhibitor comprising a sulfonamide compound as an active ingredient, wherein the sulfonamide compound comprises:

 Formula (I)

[Wherein E is 101, 1 N (CH ₃ ) 1, 1 CH ₂ —, 1 CH ₂ CH ₂ — or 1 CH ₂ 0 1, D is 1 CH ₂ — or 1 O— , Represents a hydrogen atom or a halogen atom, and R ^2a represents a halogen atom or a trifluoromethyl group. ]

 A compound represented by

 General formula (II)

[Wherein J represents 1 O— or 1 NH—, Rib may have a hydrogen atom, a halogen atom, or a substituent d—C _6. May have an alkyl group or a substituent. Good C 〇 ₄ Alkoxy group, Ci_C ₄ alkylthio group which may have a substituent,-CF ₃ , 1 OCF ₃ , 1 S CF ₃ , Ci_C ₄ alkoxycarbonyl which may have a substituent Group, nitro group, azide group, 1 O (S0 ₂ ) CH ₃ , -N (CH ₃ ). ₂ , hydroxyl group, phenyl group, substituted phenyl group, pyridinyl group, chenyl group, furyl group, quinolinyl R ^2b is a hydrogen atom, a halogen atom, a cyano group, one CF ₃ , an optionally substituted Ci-C ₆ alkyl group, or an optionally substituted Ci group 1 C4 alkoxycarbonyl group, which may have a substituent d-C4 alkoxy group, which has a substituent Optional phenyl group or Represents an optionally substituted quinolinyl group, R ³ b represents a hydrogen atom or an optionally substituted Ci—C ₄ alkoxy group, R ⁴ b represents a hydrogen atom or a substituent Ci 1 C ₆ alkyl group which may have (provided that at least one of R ^3b and R ^4b is a hydrogen atom), R ⁵ b has a hydrogen atom, a halogen atom or a substituent. Ci_C ₆ alkyl group, 1 CF ₃ or nitro group, R ^6b may have a hydrogen atom, a halogen atom or a substituent 1 c ₆ alkyl group (provided that R ^6b has a substituent) In the case of Ci 1 C ₆ alkyl group, R ^5b is a hydrogen atom and R ^7b is a halogen atom), and R ^7b may have a halogen atom or a substituent. —CG alkyl group or one CF ₃ (wherein either R ^5b or R ⁷ b may have a substituent d — C ₆ alkyl group, or R? B force may have halogen atom or substituent

In the case of a C ₆ alkyl group, each of R ⁵ b and RSb is a hydrogen atom). ]

 A compound represented by

 Formula (III) '

 The compound represented by

 Formula (IV)

The inhibitor, which is at least one compound selected from the group consisting of compounds represented by: or a pharmacologically acceptable salt thereof or a solvate thereof. 2. The sulfonamide compound is N — [[(4-Chronophenyl) amino] Carboel] 1,2,3-dihydro_ 1 H-indene 1-5-sulfonamide, N— [[(3,4-diphenyl) amino] carbonyl]-2, 3-dihydro benzofuran 1-sunorehonamide, N— (2,4-dienol benzoinole) 1 4 _ N- (2,4-Dichlorodibenzobenole) -5-bromothiophene 2-sulfonamide and 2-sulfanilamide 5 _ at least one compound selected from the group consisting of quinoxaline, or The inhibitor according to claim 1, which is a pharmacologically acceptable salt or a solvate thereof.

 3. The sulfonamide compound is N — [[((3,4-Dichlorophenyl) amino] canoleboni ^ / le] 1,2,3-dihydrobenzofuran-5-snorefone amide and N-one (2,4-dichroic mouth. The benzoinole) is at least one compound selected from the group consisting of 1_promothiophene and 2-snolehonamide, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Inhibitors.

4. The inhibitor according to claim 1, wherein the sulfonamide compound is a sodium salt of N- (2,4-dichlorobenzoyl) 15-bromothiophene 1-2-sulfonamide.

 5. A therapeutic agent for an autoimmune disease comprising a sulfonamide compound as an active ingredient, wherein the sulfonamide compound comprises:

 Formula (I)

[Where E is _ · 0—, 1 N (CH ₃ ) —, 1 CH ₂ —, 1 CH ₂ CH ₂ — or 1 CH ₂ O1, D is 1 CH ₂ — or 10 1 R ^la represents a hydrogen atom or a halogen atom, and R ^2a represents a halogen atom or a trifluoromethyl group, respectively. ]

 A compound represented by

Formula (II) (II)

[Wherein J represents 1 O— or 1 NH—, Rib may have a hydrogen atom, a halogen atom, a substituent, or a d—C ₆ alkyl group, which may have a substituent. C i-C ₄ alkoxy groups may have a substituent CI_ C4 alkylthio, one CF _3, one OCF _3, _S CF ₃ may have a substituent CI- C4 alkoxy Shikarubo sulfonyl Group, nitro group, azide group, 1 O (S0 ₂ ) CH ₃ , -N (CH ₃ ) 2, hydroxyl group, phenyl group, substituted phenyl group, pyridyl group, chenyl group, furyl group , A quinolinyl group or a triazole group, R ^2b may have a hydrogen atom, a halogen atom, a cyano group, _CF ₃ , an optionally substituted d-C ₆ alkyl group, or an optionally substituted group C1- C4 alkoxycarbonyl group, which may have a substituent CI- C ₄ alkoxy group, which may have a substituent Enyl group or optionally quinolinyl group which may have a substituent group, R ^3b is a hydrogen atom or a substituent group may C1-C4 alkoxy group optionally having, R ^4b is a hydrogen atom or a substituent Ci—C ₆ alkyl group (provided that at least one of R 3b and R 4b is a hydrogen atom), and R ^5b may have a hydrogen atom, a halogen atom or a substituent. good Ci one C ₆ alkyl group, an CF ₃ or nitro group, R6b., the water atom, a halogen atom or an optionally substituted C] L one C ₆ alkyl group

(However, when R ^6b is an ^optionally substituted d—C ₆ alkyl group, R ⁵ b is a hydrogen atom and R ^7b is a halogen atom), R ^7b is a halogen atom, Ci 1 C ₆ alkyl group which may have a substituent or 1 CF ₃ (wherein either R 5b or R? B may have a substituent Ci 1 C ₆ alkyl which may have a substituent) Motodea Luke, or R? b force S, when a halogen atom or a substituent have good Ci one be C ₆ alkyl group, either R or Reb is, are hydrogen atoms ) Respectively. ]

A compound represented by

Formula (III)

And compounds represented by

Formula (IV)

(IV)

The therapeutic agent, which is at least one compound selected from the group consisting of compounds represented by: or a pharmacologically acceptable salt thereof or a solvate thereof. Sulfonamide compounds are N-[[((4 chlorophenyl) amino] carbonyl] 1 2,3-dihydro 1 H-indene 1-5-sulfonamide, N— [[((3,4-dichloro Mouth phenyl) amino] carbonyl]-2, 3-dihydrobenzofuran 1-snorehonamide, N- (2,4-dichloro-benzophenol) 1

4_Black-and-white feninoles horn amide, N— (2, 4-Dichloro-mouthed benzoinole)-

At least one compound selected from the group consisting of 5-bromothiophene 2-snorephone amide and 2-snorephanino rare amide 5-black mouth quinoxaline, or a pharmacologically acceptable salt thereof or a solvate thereof. The therapeutic agent according to claim 5. .

Sulfonamide compounds are N — [[((3,4-dichlorophenyl) amino] carbonyl] 1,2,3-dihydrobenzofuran 1-sulfonamide and N- (2,4-dichlorobenzobenole) The treatment according to claim 5, which is at least one compound selected from the group consisting of 1-promothiophene 1-snorephoneamide, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Agent. 6. The therapeutic agent according to claim 5, wherein the sulfonamide compound is a sodium salt of N— (2,4-dichlorodibenzo) 1-5-promothiophene 1-2-sulfonamide.

9. The autoimmune disease is at least one selected from the group consisting of cellular autoimmune disease, rheumatism, multiple sclerosis, neuroautoimmune disease, insulin-dependent diabetes mellitus, systemic lupus erythematosus, inflammatory bowel disease and siedallen syndrome. The therapeutic agent according to any one of claims 5 to 8, which is one disease.

 10. A kit for treating multiple sclerosis comprising the therapeutic agent according to any one of claims 5 to 8 and a pharmaceutical composition having a nerve cell protecting action.

11. A method for inhibiting lymphocyte activation, comprising administering a sulfonamide compound to a patient, comprising:

 The sulfonamide compound is

 Formula (I)

[Wherein E is 1 O—, 1 N (CH ₃ ) 1, 1 CH ₂ —, 1 CH ₂ CH ₂ — or 1 CH ₂ 0—, D is 1 CH ₂ — or 1 O— R ^la represents a hydrogen atom or a halogen atom, and R ^2a represents a halogen atom or a tri-fluoromethyl group, respectively. ]

 A compound represented by

 General formula (Π)

[Wherein J represents 1 O— or 1 NH—, Rib represents a hydrogen atom, a halogen atom, an optionally substituted Ci_C ₆ alkyl group, or an optionally substituted Ci —C alkoxy group, optionally substituted Ci 1 C4 alkylthio group, 1 CF ₃ , 1 OCF ₃ , 1 S CF ₃ , optionally substituted Ci_C4 alkoxycarbonyl group, nitro Group, azido group, 1 O (S0 ₂ ) CH ₃ , 1 N (CH ₃ ) 2, Hydroxyl group, phenyl group, substituted phenyl group, pyridinyl group, chenyl group, furyl group, quinolyl group or triazole group, R ^2b is a hydrogen atom, halogen atom, cyano group, _CF ₃ , substituted Ci 1 C ₆ alkyl group which may have a group, Ci—C ₄ alkoxycarbonyl group which may have a substituent, Ci 1 C4 alkoxy group which may have a substituent, An optionally substituted phenyl group or an optionally substituted quinolinyl group, R ^3b is a hydrogen atom or a Ci-C4 alkoxy group optionally having a substituent, R ^4b is Ci—C ₆ alkyl group (provided that at least one of R 3b and R 4b is a hydrogen atom) which may have a hydrogen atom or a substituent, R ^5b represents a hydrogen atom, a halogen atom or a substituent. Ci-C ₆ alkyl group, which may have 1 CF ₃ or a nitro group, R ^6b is a hydrogen atom, a halogen atom, or a Ci-C ₆ alkyl group which may have a substituent (note that R ⁶ b may have a substituent). A good d-Ce alkyl group, R ^5b is a hydrogen atom and R ^7b is a halogen atom), R ^7b is a halogen atom, a C 1 -Ce alkyl group optionally having a substituent or CF ₃ (wherein either R ⁵ b or R? B is an optionally substituted Ci 1 C ₆ alkyl group, or R ^7b force is a halogen atom or substituent. In the case of a d—C ₆ alkyl group which may be present, each of R ⁵ b and R is a hydrogen atom). ]

A compound represented by

Formula (III)

The compound represented by

Formula (IV)

Or at least one compound selected from the group consisting of compounds represented by: or a pharmacologically acceptable salt thereof or a solvate thereof.

1 2. The sulfonamide compound is N — [[(4-chlorophenol) amino] carbonyl] — 2,3-dihydro 1 H—indene 1-5-sulfonamide, N—

[[(3,4-Dichlorophenyl) amino] carbonyl] 1,2,3-dihydrobenzofuran, 5-snorehon amide, N— (2,4-dichlorophenobenzo) At least one compound selected from the group consisting of an amide, N— (2,4-dioctylbenzo), 5-bromothiophene, 2-sulfonamide, and 2-sulfanyl amide, 5-cloquinoquinoline, Or a pharmaceutically acceptable salt thereof or a solvate thereof.

1 3. Sulfonamide compounds are N-[[((3,4-dichlorophenyl) amino] carbonyl] -1,3-dihydrobenzofuran 5-Snorephone amide and N- (2,4-Dichloro Benzoinole) is at least one compound selected from the group consisting of 1-bromothiophene 2-sunorephonamide, or a pharmaceutically acceptable salt thereof, or a solvate thereof. how _ώ described

 14. The method according to claim 11, wherein the sulfonamide compound is a sodium salt of (— (2,4-diclonal benzoyl) 15-bucc motifene-2-sulfonamide.

 1 5. A method of treating an autoimmune disease characterized by administering a sulfonamide compound to a patient,

 The sulfonamide compound is

Formula (I)

[Wherein E is 1 O—, 1 N (CH ₃ ) 1, 1 CH ₂ —, _CH ₂ CH ₂ — or 1 CH ₂ O1, D is 1 CH ₂ _ or 11 R ^la means a hydrogen atom or a halogen atom, and R ^2a means a halogen atom or a trifluoromethyl group. ]

A compound represented by

General formula (Π)

[Wherein, J is 1__ or 1 NH—, Rib is a hydrogen atom, a halogen atom, an optionally substituted d-Ce alkyl group, or an optionally substituted C 1—C4 alkoxy group, Ci 1 C ₄ alkylthio group which may have a substituent, 1 CF ₃ , 1 OCF ₃ , 1 S CF ₃ , Ci 1 C4 alkoxycarbonyl which may have a substituent group, a nitro group, azido group, ten (S_〇 _{2) CH 3, -N (CH} 3) 2, hydroxyl, Fuweniru group, Hue alkenyl group having a substituent, a pyridinyl group, thienyl group, furyl group, quinolinyl A group or a triazole group, R ^2b is a hydrogen atom, a halogen atom, a cyano group, 1 CF ₃ , an optionally substituted d-C ₆ alkyl group, or an optionally substituted group good one C4 alkoxycarbonyl group, an optionally substituted Ci_C ₄ alkoxy group, have chromatic 'substituents Also good phenyl group or optionally quinolinyl group which may have a substituent group, R ^3b is a hydrogen atom or a substituent and may have a d-C4 alkoxy group, R ^4b is a hydrogen atom or a substituent good d-Ce alkyl group which may have a group (provided that one at least of R3b and R4b represents a hydrogen atom) and, R ^5b is a hydrogen atom, a halogen atom, optionally have a substituent May be Ci-Ce alkyl group, _C F ₃ or nitro group, R6b is water D—c ₆ alkyl group which may have an elementary atom, a halogen atom or a substituent

(However, when R ⁶ b is an optionally substituted Cl-C ₆ alkyl group, R ⁵ b is a hydrogen atom, R ^7b is a hydrogen atom), R ^7b is A halogen atom, which may have a substituent d—C ₆ alkyl group or one CF ₃ (wherein either R or R ⁷ b may have a substituent Ci—C Force that is ₆ alkyl group, or R? B force In the case of a Ci_C ₆ alkyl group that may have a halogen atom or a substituent, either R ^5b or R ^6b is a hydrogen atom Means). ]

A compound represented by

Formula (III)

A compound represented by

Formula (IV)

Or at least one compound selected from the group consisting of compounds represented by: or a pharmacologically acceptable salt thereof or a solvate thereof. 6. The sulfonamide compound is N — [[((4 monophenyl) amino) carbonyl] 1,2,3-dihydrol 1 H-indene 1-5-sulfonamide, N— [[(3, 4— Diclonal Methyl) Amino] Carbonyl] —2, 3—Dihydrobenzofuran 1-Snorephone Amid, N— (2, 4-Dichlorobenzene Benzoinore) 1 4 _Kuroguchi Pheninores Norephone Amid, N— ( 2,4-dicyclophenobenzene) at least one compound selected from the group consisting of 1-bromothiophene 2-sulfonamide and 2-sulfanilamide 5-cloquinoquinoline, Or a pharmacologically acceptable salt thereof or a solvate thereof.

15. The method according to 15. .

 1 7. Sulfonamide compounds are N-[[((3,4-Dichlorophenyl) amino] carboninole] 1,3-Dihydrobenzofuran 5-Snorephone amide and N— (2, (4) -dichlorobenzoinole) (1) 5-promothiophene (1) 2-snolehonamide, or at least one compound selected from the group consisting of pharmaceutically acceptable salts or solvates thereof, The method described in Item 15.

 1 8. The method according to claim 15, wherein the sulfonamide compound is a sodium salt of N- (2,4-dichlorodibenzo) 1-5-bumochiophene 2-sulfonamide.

 19. The autoimmune disease is at least one selected from the group consisting of cellular autoimmune disease, rheumatism, multiple sclerosis, neuroautoimmune disease, insulin-dependent diabetes mellitus, systemic erythematosus, inflammatory bowel disease and siedallen syndrome. The method according to any one of claims 15 to 18, wherein the disease is one disease.

 20. A method for treating multiple sclerosis, comprising administering to the patient the therapeutic agent according to any one of claims 5 to 8 and a pharmaceutical composition having a nerve cell protecting action. 21. Use of a sulfonamide compound for the manufacture of a lymphocyte activation inhibitor,

 The sulfonamide compound is:

 Formula (I)

[Wherein E is 1 O—, 1 N (CH ₃ ) 1, _CH ₂ —, 1 CH ₂ CH ₂ — or 1 CH ₂ 0—, D is 1 CH ₂ — or 1 O—, Ria represents a hydrogen atom or a halogen atom, and R ² a represents a halogen atom or a trifluoromethyl group. Taste. ]

A compound represented by

Formula (II)

[Wherein J represents 101 or NH, Rib represents a hydrogen atom, a halogen atom, an optionally substituted Ci—C ₆ alkyl group, or an optionally substituted group. C 1 C 4 alkoxy group, optionally substituted Ci 1 C 4 alkylthio group, 1 CF ₃ , 1 OCF ₃ , _S CF ₃ , optionally substituted C 1 — C 4 alkoxycarbonyl group , Nitro group, azide group, _0 (S0 ₂ ) CH ₃ , 1 N (CH ₃ ) 2, hydroxyl group, phenyl group, substituted phenyl group, pyridinyl group, chenyl group, furyl group, quinolinyl group or A triazole group, R 1 is a hydrogen atom, a halogen atom, a cyano group, one CF ₃ , an optionally substituted d-Ce alkyl group, an optionally substituted Ci—C4 alkoxycarbonyl Group, Ci-C4 alkoxy group which may have a substituent, Gastric phenyl group or optionally quinolinyl group which may have a substituent, - R is a hydrogen atom or may have a substituent group d-C4 alkoxy group, R ^4b is a hydrogen atom or a substituent Cl—C ₆ alkyl group (provided that at least one of R 3b and R 4b is a hydrogen atom), R ⁵ b has a hydrogen atom, a halogen atom, or a substituent. Ci_C ₆ alkyl group, _C F ₃ or nitro group, R6b may have a hydrogen atom, a halogen atom or a substituent d—C ₆ alkyl group (provided that R ^6b has a substituent when good Ci one C ₆ alkyl group which may have, R ⁵ b is a hydrogen atom, a R ^7b is a halogen atom), R ^7b represents a halogen atom, which may have a location substituent a good Ci one C ₆ alkyl group or _cf ₃ (伹, one of R ⁵ b or R? b is a substituent If a good Ci_C ₆ alkyl der even if Luke, or a R ⁷ b force halogen atom or a substituent and may have a d-C ₆ alkyl group, one of R ⁵ b or R6b Either one is a hydrogen atom Each means. ]

 A compound represented by

Formula (III)

 The compound represented by

 Formula (IV)

Or at least one compound selected from the group consisting of compounds represented by: or a pharmacologically acceptable salt thereof or a solvate thereof. 2 2. The sulfonamide compound is N — [[((4 chlorophenyl) amino] carbonyl] — 2,3-dihydryl 1 H—indene 1-5-sulfonamide, N— [[((3, 4 -Dichlorophenyl) amino] force-luponyl] —2, 3-dihydrobenzofuran 1-snorehonamide, N— (2, 4-dichlorophenobenzene) 1-4 monophenylenolenolenoamide, N — (2,4-Diclomento Benzoinore) 1-5-Promothiophene 1-Sulfonamide and 2-Sulfaninoreamide 5 · —At least one compound selected from the group consisting of: The use according to claim 21, which is a pharmacologically acceptable salt or a solvate thereof. '

2 3. The sulfonamide compound is N — [[((3,4-diphenyl) phenyl) carbonyl] -2,3-dihydrobenzofuran 5—sulfonamide and N— (2,4-dichloro 2) At least one compound selected from the group consisting of 1-bromothiophene 2-sunorephonamide, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Use of description for.

 24. Use according to claim 21, wherein the sulfonamide compound is a sodium salt of N— (2,4-dichlorodibenzo) 15-bu mochiofen-2-sulfonamide.

 25. Use of a sulfonamide compound for the manufacture of a therapeutic agent for an autoimmune disease,

 The sulfonamide compound is

 Formula (I)

[Where E is _〇_, -N (CH ₃ ) one, one CH ₂ —, one CH ₂ CH ₂ — or one CH ₂ 0_, D is — — CH ₂ — or _0— Ria means a hydrogen atom or a halogen atom, and R ^2a means a halogen atom or a trifluoromethyl group. ]

 A compound represented by

 Formula (II)

[In the formula, J represents 1 O— or 1 NH—, Rib has a hydrogen atom, a halogen atom, an optionally substituted Ci—C ₆ alkyl group, and has a substituent. also a C E one C4 alkoxy group which may have a substituent Ci-C ₄ alkylthio group, - CF _3, _OCF _3, one S CF _3, may have a substituent C1- C4 alkoxy Cicarbol group, Nitro group, Azide group, O (S0 ₂ ) CH ₃ , 1N (CH ₃ ) 2, Hydroxyl group, Phenyl group, Substitued phenyl group, Pyridinyl group, Chenyl group, Furyl group, A quinolinyl group or a triazole group, R ² b is a hydrogen atom, a halogen C atom, cyano group, mono CF ₃ , optionally substituted d—C ₆ alkyl group, optionally substituted Ci mono C4 alkoxycarbonyl group, optionally substituted A good Ci—C4 alkoxy group, an optionally substituted phenyl group or an optionally substituted quinolinyl group, R ^3b may have a hydrogen atom or a substituent d_ A C4 alkoxy group, R ^4b is a hydrogen atom or a Ci—C ₆ alkyl group optionally having a substituent (wherein at least one of R 3b and R ^4b is a hydrogen atom), R ^5b is A hydrogen atom, a halogen atom, an optionally substituted Ci 1 C ₆ alkyl group, an CF ₃ or a nitro group, R ^6b may have a hydrogen atom, a halogen atom or a substituent C] _ to one C ₆ alkyl group (伹, RGb is optionally substituted Ci_C ₆ a When kill group, R ⁵ b is a hydrogen atom, a R ^7b is a halogen atom), R ^7b represents a halogen atom, CI_ may have a location substituent C ₆ alkyl group or a CF ₃ (Note that either R ⁵ b or R? B is an optionally substituted Ci—C ₆ alkyl group, or R ^7b force has a halogen atom or a substituent. Each of R ^{5b and} R ^6b is a hydrogen atom in the case of an optional Ci—C ₆ alkyl group. ]

A compound represented by the formula:-Formula (III)

And compounds represented by

Formula (IV)

At least one compound selected from the group consisting of compounds represented by: Or a pharmacologically acceptable salt thereof or a solvate thereof.

2 6. The sulfonamide compound is N — [[((4 monophenyl) amino) carboninole] -2,3—dihydr 1 H—indene 1-5—snorephone amide, N — [[((3,4 Mouth-and-mouth phenyl) Amino] Canolepo Ninore] 1, 2, 3-dihydro benzofuran 5-Snorephone amide, N-(2, 4-jikuguchi Benzoinore)-

4—Black-headed Fennino Reshonone Amid, N— (2,4-Dichroin Benzoinole)

It is at least one compound selected from the group consisting of 5-bromothiophene 2-sulfonamide and 2-sulfanylamide 5-chloroquinoxaline, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Use according to claim 25.

 2 7. Sulfonamide compounds are N — [[((3,4-Dichlorophenyl) amino] carbonyl] —2,3-Dihydrobenzofuran 5-Snorephoneamide and N— (2,4 (1) dichlorobenzoinole) 1) 5-promothiophene 1) 2-snolehonamide, or at least one compound selected from the group consisting of pharmaceutically acceptable salts or solvates thereof. 2 Use as described in 5.

 28. The use according to claim 25, wherein the sulfonamide compound is a sodium salt of N— (2,4-dichlorodibenzo) 15-propyl mothiophene 2-sulfonamide.

2 9. The autoimmune disease is selected from the group consisting of cellular autoimmune disease, rheumatism, multiple sclerosis, neuroautoimmune disease, insulin-dependent diabetes mellitus, systemic lupus erythematosus, inflammatory bowel disease and Siedalen syndrome. The use according to any one of claims 25 to 28, which is at least one disease.

 30. Use of a sulfonamide compound for the manufacture of a kit according to claim 10.