NOVEL SULFONAMIDE DERIVATIVES

Abstract: The present invention provide the following Sulfonamide derivatives which have low toxicity and a potent effect of inhibiting tubulin polymerization. The pharmaceutical compositions containing the said compound as an active ingredient correct abnormalities in the immune system and are useful as preventives or remedies of rheumatism such as inflammatory rheumatism or as anticancer agents. That is, the present invention relates to Sulfonamide derivatives represented by the general formula(1) [wherein preferably R 1 is a lower alkyl group, R 2 , R 3 , R 4 , R 5 , R 6 may be the same or different and each independently represents a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group, an optionally substituted amino group or alkyl group. A represents any group of (1)an optionally substituted 5-membered heterocyclic group (except triazolyl group)whose ring members include at least 1 nitrogen atom and may include any atom(s) selected from the group consisting nitrogen atom, oxygen atom, and sulfur atom, (2)an optionally substituted alicyclic group, and (3)an alicyclic group whose ring members include at least 1 nitrogen atom and may include any atom(s) selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom], and the pharmaceutically acceptable salts thereof and the use thereof as a pharmaceutical composition.

Description: TECHNICAL FIELD The present invention relates to sulfonamide derivatives having tubulin polymerization inhibitory activity, and tubulin polymerization inhibitory agents, anticancer agents, and agents useful for the prevention or treatment of rheumatism such as inflammatory rheumatism containing these derivatives as the active ingredients. BACKGROUND ART Rheumatism is a refractory disease. Rheumatoid arthritis (RA) , for example, has the basal lesion in proliferation of synovial cells accompanied with abnormalities in immune system caused by various factors. RA often causes progressive dysfunctions in articulation. To prevent the dysfunctions by RA, which is considered to be an autoimmune disease, agents correcting immune abnormalities are used in combination with general antiphlogistics under the expectation of altering natural cause of RA. For the treatment of arthritis, steroidal agents such as adrenocortical hormones including cortisone, non-steroidal anti-inflammatory agents such as aspirin, piroxicam and indometacin, antirheumatic agents such as gold preparations including aurothiomalate, D-penicillamines, and immunosuppressive agents such as cyclophosphamide and azathioprine have been used. Recent Japanese reports suggest that an intermittent administration of a low dose of methotrexate(MTX) results in high efficiency and rapid response. However, it has many side effects including interstitial pneumonia, stomatitis, gastrointestinal symptoms such as nausea and vomiting, fibrous liver, and marrow suppression. Furthermore, a long term therapeutic administration may cause high infectiousness and complicated malignancy. There has been found no desirable drug which is really effective and has few side effects with respect to this disease. Although many compounds having tubulin polymerization inhibitory activity have been reported, only colchicine(an arthrifuge) and vincristine(an antineoplastic) (Cancer Reseach, vol.20,p1023,1960) among them are applicable for therapeutic agents. Rheumacon, a glycoside extracted from natural material having antirheumatic effect is reported to show tubulin polymerization inhibitory effect(British Journal of Rheumatology, Vol.32,p804,1993), but it has an unknown chemical structural formula and many side effects such as moon face, suffusion, and gastrointestinal disorder are reported. The JP Laid-Open No.39256/1993 discloses that other sulfonamides than those of the present invention are useful antineoplastics. N-[2-((4-hydroxyphenyl)amino)-3-pyridinyl]-4-methoxybenzenesulfonamide described in the publication is reported to show tubulin polymerization inhibitory effect (Cancer Research,Vol.54,p1702,1994 ). However, the above agent has severe side effects which make its continuous administration impossible, and poor sustained therapeutic effects, or no effects in some patients. The clinical therapy demands low toxic agents which can protect and remedy patients from RA through a new mechanism. Optionally substituted (benzenesulfonamidephenyl) triazole carboxamides are described in US -A- 5,840,895. These triazole derivatives are used as intermediates in the preparation of tricyclic benzazepines and benzothiazepine derivatives. Benzenesulfonamidephenyl piperidino carboxamide and benzenesulfonamidephenyl morpholino carboxamide are disclosed in Chemical Abstracts 1982; vol. 96,85186v. DISCLOSURE OF THE INVENTION For solving the above problem, the present inventors made diligent studies to achieve low toxic anticancer agents and agents useful for the prevention or treatment of rheumatism such as inflammatory rheumatism. As the result, it has been found that the novel sulfonamides derivatives having tubulin polymerization inhibitory activity as described below are little toxic, effective as anticancer agents, and useful for the prevention or treatment of rheumatism such as inflammatory rheumatism. This finding has led to the completion of the present invention. The compounds of the present invention as shown by the general formula(1) are novel(except the case that A is triazolyl in the formula(1)) and their medical uses are unknown together with the case that A is triazolyl. The present invention relates to the following(i) to (x i). (i)Sulfonamide derivatives represented by the general formula (1) (wherein R 1 represents a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a nitro group, a hydroxy group, a cyano group, a C 1 to C 8 acyl group, an optionally substituted phenoxy group, or an optionally substituted amino group; R 2 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxy group, a cyano group, a C 1 to C 8 acyl group, an optionally substituted phenoxy group, or an optionally substituted amino group; R 3 , R 4 may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxy group, a group as shown by the general formula(2) described below: ―(CH 2 ) n ―CO―R 7 (wherein R 7 represents a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, or an optionally substituted amino group, and n means an integer of 1-5), a group as shown by the general formula(3) described below: ―(CH 2 ) n ― B (wherein B represents an imidazolyl group, a triazolyl group, a tetrazolyl group, or an optionally substituted amino group, and n means any integer of 1-5), a group as shown by the general formula(4) described below: (wherein R 8 represents a lower alkyl group, a C 1 to C 5 alkyl group substituted by 1 or 2 hydroxy group(s), a C 1 to C 5 alkyl group substituted by a C 1 to C 5 alkoxycarbonyl group, a C 1 to C 5 acyl group, or a pyridyl group; R 9 represents a lower alkyl group or a hydroxy group; a and n means any integer of 0-3 and 0-6 respectively), a group as shown by the general formula(5) described below: (wherein R 9 represents a lower alkyl group or a hydroxy group; b and n means any integer of 0-3 and 0-6 respectively), a group as shown by the general formula(6) described below: (wherein R 9 resents a lower alkyl group or a hydroxy group; c and n means any integer of 0-3 and 0-6 respectively; Q represents an oxygen atom, a sulfur atom, or a group as shown by the general formula(7) described below: (wherein d means 1 or 2)), a group as shown by the general formula(8) described below : ―(CH 2 ) n ―NR 10 R 11 (wherein R 10 , R 11 may be the same or different and each independently represents a hydrogen atom, a lower alkyl group or an optionally substituted amino lower alkyl group; n means any integer of 0-6 ), a group as shown by the general formula(9) described below: ―(CH 2 ) n ―S(O) e ―R 12 (wherein R 12 represents a hydrogen atom, a lower alkyl group or an aryl group, an aralkyl group or an optionally substituted amino group; e and n means any integer of 0-3 and 0-6 respectively),or a group as shown by the general formula(10) described below: ―(CH 2 ) n ―OR 13 (wherein R 13 represents a hydrogen atom, a lower alkyl group or an acyl group, a phosphate group or an optionally substituted aminoalkyl group; and n means any integer of 1-6 ), R 5 ,R 6 may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, an acyl group, or an optionally substituted amino group; A represents any group of (1) an optionally substituted 5-membered heterocyclic group (except triazolyl)whose ring members include at least 1 nitrogen atom and may include any atom(s) selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom,(2)an optionally substituted alicyclic group, and (3)an alicyclic group whose ring members include at least 1 nitrogen atom and may include any atom(s) selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom], or the pharmaceutically acceptable salts thereof. (ii) Sulfonamide derivatives as defined in( i), wherein R 1 is a lower alkoxy group, and R 2 , R 3 , R 4 , R 5 ,and R 6 may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, or an optionally substituted amino group, or the pharmaceutically acceptable salts thereof. (iii) Sulfonamide derivatives as defined in(i), wherein R 1 is a lower alkoxy group, and R 2 , R 3 , R 4 , R 5 ,and R 6 may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, or an optionally substituted amino group, and A represents an optionally substituted 5-membered heterocyclic group (except triazolyl) whose ring members include at least 1 nitrogen atom and may include any atom(s) selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, or the pharmaceutically acceptable salts thereof. (iv) Sulfonamide derivatives as defined in any one of (i)-(iii), wherein A represents an optionally substituted isoxazolyl group, and the pharmaceutically acceptable salts thereof. ( v )Sulfonamide derivatives as defined in( iv ),wherein A represents a 4-isoxazolyl group which has at least one lower alkyl group at the 3- and 5- position, or the pharmaceutically acceptable salts thereof. (vi)Sulfonamide derivatives as defined in(iv),wherein R 1 is a lower alkoxy group which is located at the para-position, and R 2 to R 6 are hydrogen atoms, or the pharmaceutically acceptable salts thereof. ( vii )A pharmaceutical composition containing as an active ingredient the sulfonamide derivatives( including the case that R 1 is a hydrogen atom or A is triazolyl group in the general formula(1)) as defined in any one of (i)-(vi),or the pharmaceutically acceptable salts thereof. (viii) A tubulin polymerization inhibitory agent containing as an active ingredient the sulfonamide derivatives( including the case that R 1 is a hydrogen atom or A is triazolyl group in the general formula(1)) as defined in any one of(i)-(vi),or the pharmaceutically acceptable salts thereof. (ix) An anticancer agent containing as an active ingredient the sulfonamide derivatives ( including the case that R 1 is a hydrogen atom or A is triazolyl group in the general formula(1)) as defined in any one of(i)-(vi),or the pharmaceutically acceptable salts thereof. (x)A drug as a preventive or a remedy for rheumatism containing as an active ingredient the sulfonamide derivatives( including the case that R 1 is a hydrogen atom or A is triazolyl group in the general formula(1)) as defined in any one of (i)-(vi),or the pharmaceutically acceptable salts thereof. (xi) A drug as a preventive or a remedy for rheumatism as defined in (x), wherein rheumatism is inflammatory rheumatism. BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be more particularly described below. Lower alkyl groups of the present invention are C 1 -C 6 straight chain or branched alkyl groups including methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, amyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, n-hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group. These groups may have additional substituents as long as they provide no special interference. C 1 -C 4 alkyl groups are preferable, C 1 -C 3 alkyl groups are more preferable, and methyl group and ethyl group are the most preferable. Lower alkoxy groups of the present invention are C 1 -C 6 straight chain or branched alkoxy groups including methoxy group, ethoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group. These groups may have additional substituents as long as they provide no special interference. C 1 -C 4 alkoxy groups are preferable, C 1 -C 3 alkoxy groups are more preferable, and methoxy group and ethoxy group are the most preferable. Halogen atoms of the present invention includes fluorine atom, chlorine atom, and bromine atom. Substituents connected to nitrogen atoms, for example,to those found in amino groups include lower alkyl groups, and C 1 -C 8 acyl groups (including C 1 -C 8 alkoxycarbonyl group). These groups may have additional substituents as long as they provide no special interference. Optionally substituted amino groups include unsubstituted amino group, lower acylamino groups(for example, amino groups substituted with C 1 -C 4 acyl groups such as formylamino group, propionylamino group), optionally substituted alkoxycarbonylamino groups(for example, benzyloxycarbonylamino group), and mono- or di-lower alkylamino groups(for example, N,N-dimethylamino group, N,N-diethylamino group, N,N-dipropylamino group, N,N-diisopropylamino group, N,N-di-n-butylamino group). Optionally substituted aminoalkyl groups include unsubstituted aminoalkyl groups and mono- or di-lower alkyl substituted aminoalkyl groups(C 1 -C 10 ) such as N,N-diethylaminoethyl group, N,N-dimethylaminomethyl group, N,N-dimethylaminoethyl group, and N,N-dimethylaminoethyl group. Alicyclic hydrocarbon groups ( groups represented by removing one hydrogen atom from the corresponding alicyclic hydrocarbon), which are included in A of the present invention, include 3 to 10-membered alicyclic hydrocarbon groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and cycloheptyl group. 5 to 7-membered alicyclic hydrocarbon groups such as cyclohexyl group and cycloheptyl group are preferable. 5-Membered heterocyclic hydrocarbon groups having at least one nitrogen atom, which are included in A of the present invention, mean groups represented by removing one hydrogen atom from any carbon atom of the corresponding 5-membered heterocyclic hydrocarbon rings, which have at least two unsaturated bonds and contain preferably at least two heteroatoms. They include pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, and tetrazolyl group. Oxazolyl group, isoxazolyl group, and isothiazolyl group are preferable, and isoxazolyl group is more preferable. Alicyclic hydrocarbon groups having at least one nitrogen atom in the rings, which are included in A of the present invention, mean groups represented by removing one hydrogen atom from any carbon atom of the corresponding alicyclic hydrocarbon rings, which may have one unsaturated bond and contain preferably at least two heteroatoms. The heteroatom may be selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom. They include 3 to 10-membered alicyclic hydrocarbon groups having at least one nitrogen atom in the rings such as aziridinyl group, azethidinyl group, pyrrolidinyl group, piperidinyl group, oxazolinyl group, isoxazolidinyl group, thiazolidinyl group, imidazolidinyl group, and pyrazolidinyl group. Thiazolidinyl group is preferable. Substituents of the present invention bonding to any carbon atom of alkyl groups or cyclic( optionally containing hetero atom(s)) hydrocarbon groups include lower alkyl groups, lower alkoxy groups, optionally substituted amino groups, halogen atoms, nitro groups, hydroxy group, carboxyl groups, acyl groups (including optionally phenyl-substituted alkoxycarbonyl), cyano group, and phenyl group. These groups may have additional substituents as long as they provide no special interference. Lower alkyl groups are preferable for substituents of the groups A. Acyl groups of the present invention include C 1 -C 8 acyl groups such as formyl group, acetyl group, propionyl group, butyryl group, valeryl group, optionally substituted benzoyl group, and optionally substituted benzyloxycarbonyl group. Substituents bonding to the benzoyl group or the benzyloxycarbonyl group include the substituents bonding to the carbon atom as described above. Substituents bonding to optionally substituted phenoxy group of the present invention include the substituents bonding to the carbon atom as described above. Optionally substituted amino lower alkyl groups of the present invention include C 1 -C 3 alkylamino-substituted C 1 -C 3 alkyl groups, alicyclic alkylamino-substituted C 1 -C 3 alkyl groups, and aromatic amino-substituted C 1 -C 3 alkyl groups where alicyclic alkyl groups include C 3 -C 6 groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group, and aromatic groups include C 1 -C 10 groups such as phenyl group and naphthyl group. Aralkyl groups of the present invention include C 7 -C 11 groups such as benzyl group. -(CH 2 ) n -groups of the present invention include methylene group, dimethylene group, trimethylene group, and tetramethylene group. The groups as shown by the general formula (2) include carboxymethyl group, methoxycarbonylmethyl group. The groups as shown by the general formula (3) include imidazolylmethyl group, triazolylmethyl group, tetrazolylmethyl group, aminoethyl group. The groups as shown by the general formula(4) include 4-methyl-3- methylpiperidinylmethyl group. The groups as shown by the general formula(5) include 4-methyl piperidinyl methyl group. The groups as shown by the general formula(6) include 1-morpholino methyl group. The groups as shown by the general formula(8) include dimethylaminoethyl group. The groups as shown by the general formula(9) include sulfonylmethyl group. The groups as shown by the general formula (10) include hydroxy methyl group and methoxyethyl group. In the present invention, preferable groups in R 1 are lower alkoxy groups located at the para position, and each preferable group in R 2 , R 3 , R 4 ,R 5 , and R 6 is hydrogen atom. Preferable groups in A include thiazolidinyl group, C 3 -C 6 alicyclic groups, pyrrolyl group, oxazolyl group, isoxazolyl group. Particularly preferable in A is 4-isoxazolyl group, which is more preferable if it has at least one substituent at the 3- and 5-position, and is the most preferable if it has methyl group or ethyl group both at the 3- and 5- positions. Preferable 4-isoxazolyl groups are, for example, 3-methyl-4-isoxazolyl group, 3,5-dimethyl-4-isoxazolyl group, 5-ethyl-3-methyl-4-isoxazolyl group, 3-ethyl-5-methyl-4-isoxazolyl group, 3,5-diethyl-4-isoxazolyl group . Combination of these preferable groups leads to the most preferable compound among all the sulfonamide derivatives as represented by the general formula(1). Sulfonamide derivatives of the present invention may react with acids to form their salts, which are also covered by the present invention. Their salts include the salts of inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid and the salts of organic acids such as acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid. The present invention covers all the hydrates and all the optical isomers, if any. The compounds represented by the general formula(1) include: (1)N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide (2)N-[2-(4-methoxybenzenesulfonamide)phenyl]-1,3-dimethyl-4-(1H-pyrazole) carboxamide (3)N-[2-(4-methoxybenzenesulfonamide)phenyl]-2-methyl-4-thiazole carboxamide (4)N-[2-(4-methoxybenzenesulfonamide)phenyl]-3-methyl-4-isothiazole carboxamide (5)N-[2-(4-methoxybenzenesulfonamide)phenyl]-2,5-dimethyl-4-oxazole carboxamide (6)N-[2-(4-methoxybenzenesulfonamide)phenyl]-1-methyl-1H-imidazole-4-carboxamide (7)N-[2-(toluenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide (8)N-[2-(4-fluorobenzenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide (9)N-[2-(4-nitrobenzenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide (10)N-[2-(3,4-dimethoxybenzenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide (11)N-[2-(4-methoxybenzenesulfonamide)phenyl]-(L)-prolinamide (12)N-[2-(4-methoxybenzenesulfonamide)phenyl]-3,5-dimethyl-4-isoxazole carboxamide (13)N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-ethyl-4-isoxazole carboxamide (14)(±)-N-[2-(4-methoxybenzenesulfonamide)phenyl]-4-thiazolidine carboxamide (15)(±)-N-[2-(4-methoxybenzenesulfonamide)phenyl]-3-(N-methylpiperidine) carboxamide (16)N-[2-(4-methoxybenzenesulfonamide)phenyl]-(D)-prolinamide (17)N-[2-(4-methoxybenzenesulfonamide)phenyl]-4-piperidine carboxamide (18)(±)-N-[2-(4-methoxybenzenesulfonamide)phenyl]-3-piperidine carboxamide (19)(±)-N-[2-(4-methoxybenzenesulfonamide)phenyl]-2-piperidine carboxamide (20)N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-methyl-4-oxazole carboxamide (21)N-[2-(4-methoxybenzenesulfonamide)phenyl]-cyclohexyl carboxamide (22)N-[2-(4-methoxybenzenesulfonamide)phenyl]-cyclopropyl carboxamide (23)N-[2-(4-methoxybenzenesulfonamide)phenyl]-cyclobutyl carboxamide (24)N-[2-(4-methoxybenzenesulfonamide)phenyl]-cyclopentyl carboxamide (25)N-[2-(4-methoxybenzenesulfonamide)phenyl]-N-methyl-2-pyrrole carboxamide (26)N-[2-(4-methoxybenzedesulfonamide)phenyl]-3-ethyl-5-methyl-4-isoxazole carboxamide (27)N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-ethyl-3-methyl-4-isoxazole carboxamide (28)N-[2-(4-methoxybenzenesulfonamide)phenyl]-3,5-diethyl-4-isoxazole carboxamide (29)N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-isopropyl-3-methyl-4-isoxazole carboxamide (30)N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-methyl-3-phenyl-4-isoxazole carboxamide (31)N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-methyl-3-phenyl-4-isoxazole carboxamide The compounds of the present invention, which are novel and have not yet published in any documents, can be produced, for example, by the following reaction: The novel sulfonamide derivatives represented by the general formula(1) can be produced by reacting compounds as shown by general formula(11) described below, (wherein R 1 , R 2 , R 3 , R 4 , R 5 ,and R 6 have the same meaning as mentioned before) with carboxylic acids or their reactive derivatives(whose functional groups may be protected if they are not associated with the reaction) as shown by general formula (12) described below, A―Z (A has the same meaning as mentioned before, and Z represents carboxyl groups or the reactive groups derived therefrom). The reaction is preferably carried out under the presence of a base. Most of the compounds represented by the general formula(11) are known to the public, and the others can be prepared by the method which JP Laid-Open No.39256/1993 has disclosed, or its modifications. Any reactive derivatives that are generally used to form carboxamide bonds can be applied for reactive derivatives of carboxylic acids represented by the general formula(12). They include acid halides, active amides, and active esters. They may be prepared prior to the reaction or planned to form within the reaction system. The acid halides, which include acid chloride and acid bromide, can be obtained generally by reacting carboxylic acids with thionyl halogenides. For the active amides, there can be used acid amides of, for example, imidazole, pyrazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole, and benzothiazole. For the active esters, there can be used acid esters which include methyl esters, methoxymethyl esters, cyanomethyl esters, propagyl esters, 4-nitrophenyl esters, 2,4-dinitrophenyl esters, and esters of, for example, 1-hydroxybenzotriazole. The carboxylic acids represented by the general formula (12) may be reacted with the amines represented by the general formula(11) under the presence of condensation agents such as N,N'-dicyclohexylcarbodiimide(DCC) and N-cyclohexyl-N-morpholino ethylcarbodiimide. These reactions are preferably carried out in the presence of bases such as organic tertiary amines( for example, triethylamine, N,N-dimethylaniline, and pyridine). The reaction solvents, which are desirable to use if they can dissolve the reaction-associated materials and have no reaction with them, include pyridine, tetrahydrofurane, dioxane, benzene, ether, methylene chloride, dimethylformamide, toluene, and the mixture solvents consisting of two or more solvents selected therefrom. But any reaction solvents can be used with no special limitation regardless of the above mentioned examples. The reaction can be generally carried out at ambient temperature. Cooling or heating may be applied for the reaction if necessary. The reaction time is generally 5min - 20hrs, and may be determined adequately depending upon materials and reaction temperature. Deprotection such as acid treatment converts the reaction products, whose amino groups are protected, to the compounds represented by the general formula(1) which have the free amino groups. The representative compounds as shown by the general formula(11) which are raw materials for syntheses include: N-(2-aminophenyl)-4-methoxybenzenesulfonamide N-(2-aminophenyl)-4-ethoxybenzenesulfonamide N-(2-aminophenyl)-4-propoxybenzenesulfonamide N-(2-aminophenyl)-3,4-dimethoxybenzenesulfonamide N-(2-aminophenyl)-4-toluenesulfonamide N-(2-aminophenyl)-4-fluorobenzenesulfonamide N-(2-aminophenyl)-4-nitrobenzenesulfonamide The representative compounds as shown by the general formula(12) which are raw materials for syntheses include: 5-methylisoxazole-4-carboxylic acid 5-ethylisoxazole-4-carboxylic acid 3-ethyl-5-methylisoxazole-4-carboxylic acid 5-ethyl-3-methylisoxazole-4-carboxylic acid 3,5-diethylisoxazole-4-carboxylic acid 3,5-dimethylisoxazole-4-carboxylic acid 1,3-dimethyl-1H-pyrazole-4-carboxylic acid 2-methylthiazole-4-carboxylic acid 2,5-dimethyloxazole-4-carboxylic acid N-methyl-1H-imidazole-4-carboxylic acid N-(t-butoxycarbonyl)-L-proline N-(t-butoxycarbonyl)-D-proline N-(t-butoxycarbonyl)thiazolidine-4-carboxylic acid N-methylpiperidine-3-carboxylic acid N-(t-butoxycarbonyl)piperidine-4-carboxylic acid N-(t-butoxycarbonyl)piperidine-3-carboxylic acid N-(t-butoxycarbonyl)piperidine-2-carboxylic acid cyclopropane carboxylic acid cyclobutane carboxylic acid cyclopentane carboxylic acid cyclohexane carboxylic acid 1-metyl-2-pyrrole carboxylic acid The sulfonamide, derivatives represented by the general formula(1) or the pharmaceutically acceptable salts thereof may be administrated orally or parenterally( systemic or local effect) for medical use either alone or in various preparation forms such as pulver, granule, tablet, and injection manufactured by mixing with pharmaceutically acceptable additives such as vehicle, excipient, diluent, and solubilizer. Preparations should contain 0.1-100% by weight of the compounds of the present invention or the pharmaceutically acceptable salts thereof depending on the preparation forms. The doses should be determined depending on administration routes, patients' ages, and disease symptoms to protect or cure from. The dose, for example, by oral administration for an adult is 0.1mg-2,000mg/day, and is preferably 1mg-1,000mg/day in one or more times per day. The sulfonamide derivatives represented by the general formula(1) and the pharmaceutically acceptable salts thereof have tubulin polymerization inhibitory activity, and are useful as anticancer agents and preventives or remedies for rheumatism. Rheumatism herein includes, for example, inflammatory rheumatism such as rheumatoid arthritis and osteoarthritis. EXAMPLE The present invention will now be described more in details by way of examples. The efficiency of the compounds according to the present invention will be demonstrated by way of test examples with respect to pharmacological test results of the representative compounds. NMR values were measured by 200Mz NMR with tetramethylsilane set as an internal standard. EXAMPLE 1 N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide To the suspension of 5-methylisoxazole-4-carboxylic acid(2.70g, 21.3mmol)in methylene chloride(10ml)was added pyridine(3.36g, 42.5mmol) under ice-cooled nitrogen atmosphere before thionyl chloride(2.53g, 21.3mmol) was added dropwise, and then the solution was stirred at the same temperature for 30min. To the resultant solution was added the solution of N-(2-aminophenyl)-4-methoxybenzene sulfonamide(JPLaid-Open No.39256/1993)(4.93g, 17.7mmol) in methylene chloride(20ml), and the solution was left to return back to ambient temperature gradually before it was stirred overnight. The reaction solution was added to aqueous saturated sodium bicarbonate, and then subjected to extraction by chloroform. The organic layer was dried over anhydrous sodium sulfate, and then concentrated to obtain the crude crystal. It was purified by recrystallization from ethanol to yield 4.50g of the tille compound. NMR (CDCl 3 )ppm:2. 80 (3H, s), 3. 85 (3H, s), 6. 53-6. 59 (2H, m), 6. 89 (2H, d, J=9. 0Hz), 6. 94 (1 H, m), 7. 28 (1 H, dt, J=1. 5, 7. 6Hz), 7. 59 (2H, d, J=9. 0H z), 8. 08 (1H, dd, J=1. 4, 8. 2Hz), 8. 20 (1H, s), 8. 96 (1 H, br s). MS (FAB, POS)m/z:388[M+H] + . EXAMPLE 2 N-[2-(4-methoxybenzenesulfonamide)phenyl]-1,3-dimethyl-4-(1H-pyrazole) carboxamide Like the Example 1 process, 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (1.54g, 11.0mmol) was made to react with N-(2-aminophenyl)-4-methoxy benzene sulfonamide(2.70g, 10.0mmol) to yield 1.54g of the title compound. NMR (CDCl 3 )ppm:2. 54 (3H, s), 3. 84(3H, s), 3. 87 (3H, s), 6. 57 (1H, dd, J=1. 4, 7. 9Hz), 6. 81-6. 92 (3H, d+m, J=9. 0Hz), 6. 9 7 (1H, br s), 7. 20 (1H, m), 7. 59 (2H, d, J=9. 0Hz), 7. 85 (1H, s), 8. 20 (1H, dd, J=1. 4, 8. 3 Hz), 8. 65 (1 H, br s). MS (FAB, POS)m/z:401[M+H] + . EXAMPLE 3 N-[2-(4-methoxybenzenesulfonamide)phenyl]-2-methyl-4-thiazole carboxamide To the suspension of 5-methylthiazole-4-carboxylic acid(510mg, 3.6mmol)in methylene chloride(3.6ml)was added pyridine(295mg, 3.6mmol) at ambient temperature before thionyl chloride(473mg, 4.0mmol)was added dropwise. After 30min, the resultant solution was added to the solution of N-(2-aminophenyl)-4-methoxybenzenesulfonamide(1.00g,3.6mmol)in methylene chloride (7.2ml) with pyridine(378mg, 3.6mmol) further added thereto, before it was stirred overnight. To the reaction solution was added water and ethyl acetate to extract. The organic layer was washed with aqueous saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, and then concentrated to obtain the crude crystal. It was washed with diethyl ether and purified by recrystallization from isopropyl alcohol to yield 390mg of the title compound. NMR (DMSO-d 6 ) ppm:2. 79 (3H, s), 3. 77(3H, s), 6. 84 (1 H, dd, J=1. 5, 7. 9Hz), 6. 95(2H, d, J=9. 0Hz), 7. 03 (1 H, dt, J=1. 5, 7. 9Hz), 7. 28 (1H, dt, J=1. 5, 8. 2Hz), 7. 58 (2H, d, J=9. 0 Hz), 8. 13 (1H, dd, J=1. 5, 8. 2Hz) , 8. 25 (1H, s), 9. 68 (1H, br s), 10. 00 (1H, br s). MS(FAB, POS)m/z:404 [M+H] + . EXAMPLE 4 N-[2-(4-methoxybenzenesulfonamide)phenyl]-3-methyl-4-isothiazole carboxamide Like the Example 3 process, 3-methylisothiazole-4-carboxylic acid (510mg, 3.7mmol) was made to react with N-(2-aminophenyl)-4-methoxybenzene sulfonamide(1.00g, 3.6mmol) to yield 390mg of the title compound. NMR (DMSO-d 6 ) ppm:2. 56 (3H, s), 3.75 (3H, s), 6. 91 (2 H, d, J=9. 0Hz), 7. 11-7. 23 (3H, m), 7. 53 (2H, d, J=9. 0 Hz), 7. 66 (1H, d, J=7. 6Hz), 9. 41 (1H, br s), 9. 42 (1 H, s), 9. 47 (1H, br s). MS (FAB, POS)m/z:404 [M+H] + . EXAMPLE 5 N-[2-(4-methoxybenzenesulfonamide)phenyl]-2,5-dimethyl-4-oxazole carboxamide Like the Example 1 process, 2,5-dimethyloxazole-4-carboxylic acid (1.40g, 9.9mmol) was made to react with N-(2-aminophenyl)-4-methoxybenzene sulfonamide(2.50g, 9.0mmol) to yield 1.90g of the title compound. NMR (CDCl 3 )ppm:2. 45(3H, s), 2. 64 (3H, s), 3. 80 (3H, s), 6. 76 (2H, d, J=9. 0 Hz), 7. 11-7. 42 (4H, m), 7. 56 (2H, d, J=9. 0Hz), 7. 7 6 (1H, br s), 8. 6 2 (1H, br s). MS (FAB,POS)m/z:402 [M+H] + . EXAMPLE 6 N-[2-(4-methoxybenzenesulfonamide)phenyl]-1-methyl-1H-imidazole-4-carboxamide To the suspension of N-methyl-1H-imidazole-4-carboxylic acid(594mg, 3.3mmol)in methylene chloride(3ml) was added pyridine(569mg, 7.2mmol) under ice-cooled nitrogen atmosphere before thionyl chloride(428mg, 3.6mmol) was added dropwise, and then the solution was stirred at the same temperature for 30min. To the resultant solution was added the solution of N-(2-aminophenyl)-4-methoxy benzenesulfonamide(834mg, 3.0mmol) in methylene chloride(3ml), and the solution was left to return back to ambient temperature gradually before it was stirred overnight. The reaction solution was added to aqueous saturated sodium bicarbonate, and then subjected to extraction by chloroform. The organic layer was dried over anhydrous sodium sulfate, and then concentrated to obtain the residue. It was purified by silicagel chromatography (chloroform:methanol=19:1) to yield 100mg of the title compound. NMR (DMSO-d 6 ) ppm: 3. 74 (3H, d, J=4. 2Hz), 3. 80 (3H, s), 6. 67 (1 H, dd, J=1. 3, 7. 9Hz), 6. 88-7. 09 (3H, d+m, J= 8. 9 Hz), 7. 18-7. 37 (2H, m), 7. 61 (2H, d, J=8. 9Hz), 7. 75-7. 85 (3H, m), 8. 22 (1H, dd, J=1. 3, 8. 2Hz), 9. 63 (1 H, br s), 9. 88 (1H, br s). MS (FAB, POS) m/z : 387[M+H] + . EXAMPLE 7 N-[2-(p-toluenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide Like the Example 1 process, 5-methylisoxazole-4-carboxylic acid (667mg, 5.3mmol) was made to react with N-(2-aminophenyl)-4-toluene sulfonamide(1.31g, 5.0mmol) to yield 1.19g of the title compound. NMR (DMSO-d 6 ) ppm: 2. 29 (3 H, s), 2. 67 (3H, s), 7. 13-7. 25 (5H, d+m, J=8. 3Hz), 7. 45-7. 55 (3H, d+m, J=8. 3Hz), 8. 82 (1 H, s), 9. 30 (1 H, s), 9. 44 (1H, s). MS(FAB,POS)m/z:372[M+H] + . EXAMPLE 8 (Reference) N-[2-(benzenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide Like the Example 1 process, 5-methylisoxazole-4-carboxylic acid (667mg, 5.3mmol) was made to react with N-(2-aminophenyl)-benzene sulfonamide(1.23g, 5.0mmol) to yield 690mg of the title compound. NMR (DMSO-d 6 ) ppm: 2. 66 (3H, s), 7. 14-7. 26 (3H, m), 7. 37-7. 65 (6H, m), 8. 84(1H, s), 9. 32(1H, s), 9. 56 (1H, s). MS (FAB, POS)m/z:358 [M+H] + . EXAMPLE 9 N-[2-(4-fluorobenzenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide Like the Example 1 process, 5-methylisoxazole-4-carboxylic acid (667mg, 5.3mmol) was made to react with N-(2-aminophenyl)-4-fluorobenzene sulfonamide (1.33g, 5.0mmol)to yield 300mg of the title compound. NMR (DMSO-d 6 ) ppm : 2. 66 (3H, s), 7. 16-7. 28 (5H, m), 7. 4 9 (1H, m), 7. 59-7. 69(2H, m), 8. 85 (1H, s), 9. 31 (1H, br s), 9. 56 (1H, br s). MS (FAB, POS) m/z : 376 [M+H] + . EXAMPLE 10 N-[2-(4-nitrobenzenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide Like the Example 1 process, 5-methylisoxazole-4-carboxylic acid (667mg, 5.3mmol) was made to react with N-(2-aminophenyl)-4-nitrobenzene sulfonamide (1.46g, 5.0mmol) to yield 330mg of the title compound. NMR (DMSO-d 6 ) ppm : 2. 59 (3H, s), 7. 20-7. 33 (3H, m), 7. 43 (1H, m), 7. 81(2H, d, J=8. 8Hz), 8. 21 (2H, d, J=8. 8 Hz), 8. 82 (1H, s), 9. 27 (1H, br s), 9. 80 (1H, br s). MS(FAB,POS)m/z:403[M+H] + . EXAMPLE 11 N-[2-(3,4-dimethoxybenzenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide Like the Example 6 process, 5-methylisoxazole-4-carboxylic acid (667mg, 5.3mmol) was made to react with N-(2-aminophenyl)-3,4-dimethoxybenzene sulfonamide (1.54g, 5.0mmol) to yield 750mg of the title compound. NMR (DMSO-d 6 ) ppm: 2. 6 3 (3 H, s), 3. 5 6 (3H, s), 3. 75(3 H, s), 6. 89 (1H, d, J=8. 6Hz), 6. 97 (1H, d, J=2. 2Hz), 7. 10-7. 31 (5 H, m), 7. 50 (1H, m), 8. 80 (1H, s), 9. 2 3 (1 H, s), 9. 32 (1H, s). MS (FAB, POS)m/z:418 [M+H] + . EXAMPLE 12 N-[2-(4-methoxybenzenesulfonamide)phenyl]-(L)-prolinamide HCl salt To the suspension of N-(t-butoxycarbonyl)-L-prolin(474mg, 2.2mmol)in methylene chloride(5ml)was added pyridine(348mg, 4.4mmol) under ice-cooled nitrogen atmosphere before thionyl chloride(367mg, 2.2mmol)was added dropwise, and then the solution was stirred at the same temperature for 30min. To the resultant solution was added the solution of N-(2-aminophenyl)-4-methoxybenzenesulfonamide(556mg, 2.0mmol), and the solution was left to return back to ambient temperature gradually before it was stirred overnight. The reaction solution was concentrated to obtain the residue, to which 4N-HCl/dioxane(5.0ml,20.0mmol)was added before it was stirred at ambient temperature for 2hrs. The reaction solution was concentrated to obtain the residue, which was purified by silicagel chromatography (chloroform : methanol =19:1)and HP-20(0 to 90% aqueous methanol solution) to yield 210mg of the title compound. NMR (CD 3 OD) ppm: 2. 05-2. 22(2H, m), 2. 31 (1 H, m), 2. 5 5 (1 H, m), 3. 34-3. 55(2H, m), 3. 86 (3H, s), 4. 55(1 H, t, J=8. 0Hz), 6. 70 (1H, d, J=7. 9Hz), 7. 00 (2H, d, J=8. 9Hz), 7. 0 2 (1H, m), 7. 25(1 H, m), 7. 58 (2H, d, J=8. 9 H z), 7. 78(1H, m). MS (FAB, POS) m/z: 376 [M+H] + . EXAMPLE 13 N-[2-(4-methoxybenzenesulfonamide)phenyl]-3,5-dimethyl-4-isoxazole carboxamide Like the Example 6 process, 3,5-dimethylisoxazole-4-carboxylic acid (846mg, 6.0mmol) was made to react with N-(2-aminophenyl)-4-methoxybenzene sulfonamide (1.39g, 5.0mmol) to yield 600mg of the title compound. NMR (DMSO-d 6 ) ppm: 2.41(3H, s), 2. 63 (3H, s), 3. 82 (3 H, s), 6. 83 (1H, dd, J=1. 4, 8. 0 Hz), 6. 99-7. 09 (3H, m), 7. 22 (1H, dt, J=1. 5, 8. 0Hz), 7. 60 (2H, d, J=9. 0Hz), 7. 86 (s), 9. 10 (1H, brs), 9. 49(1H, brs). MS (FAB, POS)m/z : 402 [M+H] + . EXAMPLE 14 N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-ethyl-4-isoxazole carboxamide Like the Example 1 process, 5-ethylisoxazole-4-carboxylic acid (846mg, 6.0mmol) was made to react with N-(2-aminophenyl)-4-methoxybenzene sulfonamide (1.39g, 5.0mmol) to yield 1.04g of the title compound. NMR (CDCl 3 ) ppm: 1. 39 (3H, t, J=7. 6Hz), 3. 23 (2H, q, J =7. 6Hz), 3. 85 (3H, s), 6. 58 (1H, dd, J=1. 4, 8. 0Hz), 6. 63 (1H, s), 6. 89 (2H, d, J=9. 0Hz), 6. 94 (1H, dt, J= 1. 5, 7. 7Hz), 7. 28 (1H, m), 7. 58 (2H, d, J=9. 0Hz), 8. 07 (1H, dd, J=1. 4, 8. 0Hz), 8. 60(1H, br s). MS (FAB,POS)m/z:402[M+H] + . EXAMPLE 15 (±)-N-[2-(4-methoxybenzenesulfonamide)phenyl]-4-thiazolidine carboxamide HCl salt To the suspension of N-(t-butoxycarbonyl)thiazolidine-4-carboxylic acid(1.0g, 6.0mmol)in methylene chloride(10ml)was added pyridine(1.02g, 12.0mmol) under ice-cooled nitrogen atmosphere before thionyl chloride(718mg, 6.0mmol)was added dropwise, and then the solution was stirred at the same temperature for 30min. To the resultant solution was added the solution of N-(2-aminophenyl)-4-methoxy benzenesulfonamide(1.39g, 5.0mmol), and the solution was left to return back to ambient temperature gradually before it was stirred overnight. The reaction solution was concentrated to obtain the residue, to which ethyl acetate and aqueous saturated sodium bicarbonate were added to extract. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the residue, which was purified by silicagel chromatography (chloroform : methanol =19:1). To the resultant residue was added 4N-HCl/dioxane(12.5ml,50.0mmol) before it was stirred at ambient temperature for 2hrs. The reaction solution was concentrated to obtain the crude crystal, which was purified by recrystallization from methanol to yield 1.05g of the title compound. NMR (CD 3 OD) ppm: 3. 11 (1H, dd, J=7. 5, 10. 7Hz), 3. 40 (1 H, dd, J=4. 0, 1 0. 7Hz), 3. 86 (3H, s), 4. 1 6 (1 H, d, J=9. 7Hz), 4. 32 (1 H, d, J=9. 7Hz), 4. 33(1 H, dd, J=2. 0, 7. 5Hz), 6. 64 (1 H, dd, J=1. 5, 7. 0Hz), 6. 90-7. 04(3 H, m +d, J=9. 0Hz), 7. 24(1H, dt, J=1. 5, 8. 0 Hz), 7. 59 (2H, d, J=9. 0Hz), 8. 02 (1H, dd, J=1. 4, 8. 0Hz). MS (FAB, POS) m/z: 394 [M+H] + . EXAMPLE 16 (±)-N-[2-(4-methoxybenzenesulfonamide)phenyl]-3-(N-methyl piperidine) carboxamide HCl salt To the suspension of N-methylpiperidine-3-carboxylic acid(537mg, 3.0mmol)in methylene chloride(10ml)was added pyridine(767mg, 9.0mmol) under ice-cooled nitrogen atmosphere beforethionyl chloride(359mg, 3 .0mmol)was added dropwise, and then the solution was stirred at the same temperature for 30min. To the resultant solution was added the solution of N-(2-aminophenyl)-4-methoxy benzenesulfonamide(695mg, 2.5mmol), and the solution was left to return back to ambient temperature gradually before it was stirred overnight. The reaction solution was concentrated to obtain the residue, which was purified by HP-20 (gradient with 0 to 90% aqueous mathanol solution) to yield 550mg of the title compound. NMR (DMSO-d 6 ) ppm: 1. 42 (1H, m), 1. 80-2. 02 (3H, m), 2. 79 (3H, d, J=3. 4Hz), 2. 85-3. 50 (5H, m), 3. 82 (3H, s), 7. 01-7. 20 (5H, d+m, J=9. 0Hz), 7. 51-7. 59 (3H, m+d, J=9. 0Hz), 9.45 (1H, br s), 9. 65 (1H, br s). MS (FAB, POS)m/z:440 [M+H] + . EXAMPLE 17 N-[2-(4-methoxybenzenesulfonamide)phenyl]-(D)-prolinamide HCl salt: Like the Example 12 process, N-(t-butoxycarbonyl)-D-prolin(1.29g, 6.0mmol) was made to react with N-(2-aminophenyl)-4-methoxybenzene sulfonamide (1.39g, 5.0mmol) to yield 150mg of the title compound. NMR (CD 3 OD) ppm: 1. 90-2. 08 (2H, m), 2. 1 6 (1 H, m) 2. 42 (1 H, m), 3. 20-3. 36 (2H, m), 3. 87 (3H, s), 4. 23 (1 H, d d, J=6. 0, 8. 9Hz), 6. 68 (1 H, dd, J=1. 5, 8. 0Hz), 6. 94 -7. 03 (3H, d+m, J=9. 0Hz), 7. 25 (1 H, dt, J=1. 5, 8. 0H z), 7. 59 (2H, d, J=9. 0 Hz), 7. 90 (1 H, dd, J=1. 4, 8. 2H z). MS (FAB, POS) m/z : 376 [M+H] + . EXAMPLE 18 N-[2-(4-methoxybenzenesulfonamide)phenyl]-4-piperidine carboxamide HCl salt: To the suspension of N-(t-butoxycarbonyl)piperidine-4-carboxylic acid(1.38g, 6.0mmol)in methylene chloride(20ml)was added pyridine(1.02g, 12.0mmol) under ice-cooled nitrogen atmosphere before thionyl chloride(718mg, 6.0mmol)was added dropwise, and then the solution was stirred at the same temperature for 30min. To the resultant solution was added the solution of N-(2-aminophenyl)-4-methoxy benzenesulfonamide(1.39g, 5.0mmol) , and the solution was left to return back to ambient temperature gradually before it was stirred overnight. The reaction solution was concentrated to obtain the residue, to which ethyl acetate and aqueous saturated sodium bicarbonate were added to extract. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the residue, to which 4N-HCl/dioxane (15.0ml,60.0mmol) was added before it was stirred at ambient temperature for 2hrs. The reaction solution was concentrated to obtain the crude crystal, which was washed with isopropyl alcohol to yield 1.52g of the title compound. NMR (DMSO-d 6 ) ppm:1. 67-2. 00 (4H, m), 2. 61(1 H, m), 2. 83-3. 06 (2H, m) 3. 25-3. 44(3H, m), 3. 80 (3H, s), 6. 9 7-7. 20 (5H, d+m, J=8. 9Hz), 7. 55 (2H, d, J=8. 9Hz), 7. 64 (1 H, d, J=7. 7Hz), 8. 65 (1 H, br s), 8. 90 (1 H, br s). MS (FAB, POS)m/z:390 [M+H] + . EXAMPLE 19 (±)-N-[2-(4-methoxybenzenesulfonamide)phenyl]-3-piperidine carboxamide HCl salt: Like the Example 18 process, N-(t-butoxycarbonyl) piperidine-3-carboxylic acid(1.38g, 6.0mmol) was made to react with N-(2-aminophenyl)-4-methoxybenzene sulfonamide (1.39g, 5.0mmol) to yield 900mg of the title compound, where the corresponding residue was purified by silicagel chromatography (chloroform : methanol =19:1) and HP-20(gradient with 0 to 90% aqueous methanol solution). NMR (CD 3 OD) ppm: 1. 82-2. 21(5H, m), 2. 91-3. 48 (4H, m), 3. 86 (3H, s), 6. 84 (1 H, dd, J=1. 5, 7. 9Hz), 6. 98 (2H, d, J=8. 9 Hz), 7. 04 (1 H, dt, J=1. 5, 7. 9 Hz), 7. 23 (1 H, dt, J=1. 4, 8. 0 Hz), 7. 56 (2H, d, J=8. 9 Hz), 7. 6 9 (1H, dd, J=1. 4, 8. 0Hz). MS (FAB,POS)m/z:390[M+H] + . EXAMPLE 20 (±)-N-[2-(4-methoxybenzenesulfonamide)phenyl]-2-piperidine carboxamide HCl salt Like the Example 18 process, N-(t-butoxycarbonyl) piperidine-3-carboxylic acid(1.38g, 6.0mmol) was made to react with N-(2-aminophenyl)-4-methoxybenzenesulfonamide(1.39g,5.0mmol) to yield 1.24g of the title compound, where the corresponding residue was purified by HP-20(gradient with 0 to 90% aqueous methanol solution). NMR (CD 3 OD) ppm: 1. 65-2. 07 (5H, m), 2. 42 (1H, m), 3. 0 9 (1H, m), 3. 45(1H, m), 3. 85 (3H, s), 4. 1 0 (1H, m), 6. 70 (1H, dd, J=1. 5, 7. 9Hz), 6. 99 (2H, d, J=9. 0Hz),7. 02 (1H, m), 7. 25 (1H, dt, J=1. 5, 8. 0Hz), 7. 59(2H, d, J=9. 0Hz), 7. 83 (1H, dt, J=1. 4, 8. 0Hz). MS (FAB, POS)m/z : 390 [M+H] + . EXAMPLE 21 N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-methyl-4-oxazole carboxamide Like the Example 1 process, 5-methyloxazole-4-carboxylic acid (315mg, 2.5mmol) was made to react with N-(2-aminophenyl)-4-methoxybenzene sulfonamide(584mg, 2.1mmol) to yield 430mg of the title compound. NMR (DMSO-d 6 ) ppm: 2.64 (3H, s), 3. 80 (3H, s), 6. 76 (1 H, dd, J=1. 4, 7. 9Hz), 6. 94 (2H, d, J=9. 0 Hz), 6. 98 (1 H, dt, J=1. 5, 7. 9 Hz), 7. 24 (1H, dt, J=1. 5, 8. 2Hz), 7. 56 (2H, d, J=9. 0Hz), 8. 11 (1H, dd, J=1. 4, 8. 2 Hz), 8. 42 (1H, s), 9. 63 (1H, br s), 9. 75 (1H, br s). MS(FAB, POS) m/z : 388 [M+H] + . EXAMPLE 22 N-[2-(4-methoxybenzenesulfonamide)phenyl]-cyclohexyl carboxamide To the solution of N-(2-aminophenyl)-4-methoxybenzene sulfonamide(1.39g, 5.0mmol) in tetrahydrofuran(20ml) was dropwise added cyclohexane carbonyl chloride(748mg, 5.1mmol)under ice-cooled nitrogen atmosphere, and then the solution was left to return back to ambient temperature gradually before it was stirred overnight. The reaction solution was concentrated to obtain the residue, which was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, and concentrated to obtain the crude crystal, which was purified by recrystallization from ethanol to yield 1.10g of the title compound. NMR (DMSO-d 6 ) ppm: 1. 16-1. 43 (5H, m), 1. 60-1. 83 (5H, m), 2. 16 (1 H, m), 3. 81 (3H, s), 6. 95-7. 20 (5H, m+d, J =8. 8 Hz), 7. 46-7. 67 (3H, m+d, J=8. 8 Hz), 9. 02 (1 H, s), 9. 23(1H, s). MS (FAB, POS) m/z : 389 [M+H] + . EXAMPLE 23 N-[2-(4-methoxybenzenesulfonamide)phenyl]-cyclopropyl carboxamide Like the Example 22 process, N-(2-aminophenyl)-4-methoxybenzene sulfonamide(1.39g, 5.0mmol) was made to react with cyclopropane carbonyl chloride(533mg, 5.1mmol) to yield 820mg of the title compound. NMR (DMSO-d 6 ) ppm: 0. 75-0. 86 (4H, m), 1. 60 (1H, m), 3. 80 (3H, s), 6. 99 (2H, d, J=9. 0), 7. 05-7. 20 (3H, m), 7. 45-7. 54 (3H, m), 9. 20 (1H, br s), 9. 45 (1H, br s). MS (FAB, POS)m/z:347[M+H] + . EXAMPLE 24 N-[2-(4-methoxybenzenesulfonamide)phenyl]-cyclobutyl carboxamide Like the Example 22 process, N-(2-aminophenyl)-4-methoxybenzene sulfonamide(1.39g, 5.0mmol) was made to react with cyclobutane carbonyl chloride(597mg, 5.1mmol) to yield 1.54g of the title compound. NMR (DMSO-d 6 ) ppm: 1. 75-2. 25 (6H, m), 3. 1 0 (1H, m), 3. 79 (3H, s), 6. 97-7. 22 (5H, m), 7. 43-7. 60 (3H, m), 9. 00 (1H, br s), 9. 28 (1 H, br s). MS (FAB, POS)m/z:361 [M+H] + . EXAMPLE 25 N-[2-(4-methoxybenzenesulfonamide)phenyl]-cyclopentyl carboxamide Like the Example 22 process, N-(2-aminophenyl)-4-methoxybenzene sulfonamide(1.39g, 5.0mmol) was made to react with cyclopentane carbonyl chloride(666mg, 5.1mmol) to yield 1.02g of the title compound. NMR (DMSO-d6) ppm:1. 50-1. 90 (8H, m), 2. 65(1H, m), 3. 80 (3H, s), 6. 97-7. 22 (5H, m), 7. 46-7. 62 (3H, m), 9. 15 (1H, br s), 9. 26 (1H, br s). MS (FAB, POS)m/z:375 [M+H]+. EXAMPLE 26 N-[2-(4-methoxybenzenesulfonamide)phenyl]-N-methyl-2-pyrrole carboxamide Like the Example 1 process, 1-methyl-2-pyrrole carboxylic acid (625mg, 5.0mmol) was made to react with N-(2-aminophenyl)-4-methoxybenzene sulfonamide(1.39g, 5.0mmol) to yield 1.55g of the title compound. NMR (DMSO-d6) ppm: 3. 77 (3H, s), 3. 84 (3H, s), 6. 1 4 (1H, dd, J=2. 6, 4. 0 Hz), 6.84 (1H, dd, J=2. 0, 4. 0H z), 6. 93 (2H, d, J=9. 0Hz), 6. 97-7. 09 (3H, m), 7. 2 2 (1H, dt, J=2. 0, 8. 1 Hz), 7. 57 (2H, d, J=9. 0Hz), 7. 76 (1H, dd, J=1. 3, 8. 0 Hz), 9. 22 (1H, br s), 9. 54 (1 H, br s). MS (FAB, POS)m/z : 386 [M+H] + . EXAMPLE 27 N-[2-(4-methoxybenzenesulfonamide)phenyl]-3-ethyl-5-methyl-4-isoxazole carboxamide To the suspension of 3-ethyl-5-methylisoxazole-4-carboxylic acid(930mg, 6.0mmol) in methylene chloride(10ml) was added pyridine(0.97ml, 12.0mmol) under ice-cooling by stirring before thionyl chloride(0.44ml, 6.0mmol) was added dropwise. After 30min, to the resultant solution was added N-(2-aminophenyl)-4-methoxy benzenesulfonamide(1.39g, 5.0mmol) under ice-cooling, and the solution was left to return back to ambient temperature gradually before it was stirred overnight. To the reaction solution was added water and ethyl acetate to extract. The organic layer was washed with aqueous saturated sodium bicarbonate, 2N-HCl, and water ,and then dried over anhydrous magnesium sulfate. The resultant solution was concentrated to obtain the crude residue, which was purified by silicagel chromatography(hexane:ethyl acetate=2:1) to yield 1.95g of the title compound. NMR (DMSO-d6) ppm:1. 24 (3H, t, J=7. 5Hz), 2. 63 (3H, s), 2. 84 (2H, q, J=7. 5 Hz), 3. 83 (3H, s), 6. 84 (1 H, dd, J=1. 5, 7. 9 Hz), 6. 95-7. 08 (3H, m), 7. 21(1 H, d t, J=1. 5, 7. 9 Hz), 7. 60 (2H, d, J=8. 8 Hz), 7. 86 (1 H, dd, J=1. 3, 8. 1Hz), 9. 1 0 (1H, b r s), 9. 45 (1 H, br s). MS (FAB, POS)m/z:416 [M+H] + . EXAMPLE 28 N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-ethyl-3-methyl-4-isoxazole carboxamide Like the Example 27 process, 5-ethyl-3-methylisoxazole-4-carboxylic acid (930mg, 6.0mmol) was made to react with N-(2-aminophenyl)-4-methoxybenzene sulfon amide(1.39g, 5.0mmol) to yield 1.96g of the title compound. NMR (DMSO-d6) ppm: 1. 28 (3H, t, J=7. 6 Hz), 2. 43 (3H, s), 3. 04 (2H, q, J=7. 6 Hz), 3. 83 (3H, s), 6. 80 (1H, dd, J=1. 5, 7. 9 Hz), 6. 95-7. 08 (3H, m), 7. 21 (1H, d t, J=1. 5, 7. 9 Hz), 7. 60 (2H, d, J=8. 8 Hz), 7. 89 (1H, dd, J=1. 3, 8. 1 Hz), 9. 10 (1H, br s) , 9. 50 (1H, br s). MS (FAB, POS)m/z : 416 [M+H] + . EXAMPLE 29 N-[2-(4-methoxybenzenesulfonamide)phenyl]-3,5-diethyl-4-isoxazole carboxamide Like the Example 27 process, 3,5-diethyl-isoxazole-4-carboxylic acid (1.01g, 6.0mmol) was made to react with N-(2-aminophenyl)-4-methoxybenzene sulfonamide(1.39g, 5.0mmol) to yield 1.82g of the title compound. NMR (DMSO-d6) ppm:1. 25(3H, t, J=7. 7Hz), 1. 29 (3H, t, J=7. 7 Hz), 2. 85 (2H, q, J=7. 7 Hz), 3. 03 (2H, q, J =7. 7 Hz), 3. 83 (3H, s), 6. 82 (1H, dd, J=1. 5, 7. 9 Hz), 6. 96-7. 1 0 (3H, m), 7. 22 (1H, dt, J=1. 5, 7. 9Hz), 7. 60 (2H, d, J=8. 8Hz), 7. 88 (1H, dd, J=1. 3, 8. 1Hz), 9. 1 8 (1H, br s) , 9. 48 (1H, br s). MS (FAB,POS)m/z:430[M+H] + . EXAMPLE 30 N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-isopropyl-3-methyl-4-isoxazole carboxamide Like the Example 27 process, 5-isopropyl-3-methylisoxazole-4-carboxylic acid (1.01g, 6.0mmol) was made to react with N-(2-aminophenyl)-4-methoxybenzene sulfonamide(1.39g, 5.0mmol) to yield 1.59g of the title compound. NMR (DMSO-d6) ppm : 1. 31, 1. 34 (2 X 3 H, each s), 2. 4 3 (3H, s), 3. 61 (1H, m), 3. 85 (3H, s), 6. 78 (1H, dd, J=1. 5, 7. 9 Hz), 6. 96-7. 08(3H, m), 7. 22 (1H, dt, J =1. 5, 7. 9 Hz), 7. 61 (2H, d, J=9. 0 Hz), 7. 92 (1H, dd, J=1. 3, 8. 1 Hz), 9. 1 2 (1H, br s) 9, 50 (1 H, br s). MS (FAB, POS) m/z: 430 [M+H] + . EXAMPLE 31 N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-methyl-3-phenyl-4-isoxazole carboxamide Like the Example 27 process, 5-methyl-3-phenylisoxazole-4-carboxylic acid (500mg, 2.46mmol) was made to react with N-(2-aminophenyl)-4-methoxybenzene sulfonamide(570mg, 2.05mmol) to yield 400mg of the title compound. NMR (DMSO-d6)ppm:2. 41(3H, s), 3. 80 (3H, s), 6. 9 0-7. 24 (5H, m), 7. 53-7. 61 (5H, m), 7. 73-7. 88 (3H, m), 9. 33 (1H, br s), 9.70 (1H, br s). MS (FAB, POS)m/z:464 [M+H] + . EXAMPLE 32 N-[2-(4-methoxybenzenesulfonamide)phenyl]-3-methyl-5-phenyl-4-isoxazole carboxamide Like the Example 27 process, 3-methyl-5-phenylisoxazole-4-carboxylic acid (1.22g, 6.0mmol) was made to react with N-(2-aminophenyl)-4-methoxybenzene sulfonamide(1.39g, 5.0mmol) to yield 1.12g of the title compound. NMR (DMSO-d6) ppm: 2. 65 (3H, s), 3. 80 (3H, s), 6. 8 7-7. 22 (5H, m), 7. 46-7. 61(5H, m), 7. 68-7. 78 (3H, m), 9. 34(1H, br s), 9. 54 (1H, br s). MS(FAB, POS)m/z:464[M+H] + . The pharmacological effects of the compounds of the present invention will be demonstrated concretely by way of test examples. Abbreviations used in the test examples are as follows, CTP: Cytidine 5'-triphosphate EGTA: Ethylene glycol bis(2-aminoethylether) GTP: Guanosine 5'-triphosphate MES: 2-morpholinoethane sulfonic acid RB: Reaction buffer TEST EXAMPLE 1 Tubulin polymerization inhibitory test using microtubule proteins originated from swine brain: Microtubule proteins was extracted from swine brain by the Shelansky method(Tanpakusitu jikkenhou, Zoku-Seikagaku Jikken Kouza, Vol.6, "Structure and Function of Cytoskeleton" (1 st Vol.),Tokyo Kagaku Dojin). Polymerization of microtubule proteins was assayed by turbidity measurement. Warming in RB(MES:100mM, MgCl 2 :0.5mM, EGTA:1mM, pH6.8) containing GTP accelerates microtubule proteins, which are previously depolymerized in ice bath, to reconstruct microtubules, with resulting increased turbidity. Change in turbidity can be measured by an absorptiometer. The compounds of the present invention were dissolved in dimethylsulfoxide to prepare their test solutions. To 245 µl of a RB solution containing microtubule proteins(2mg/ml) and GTP(1mM) was added 5 µl of either an above test solution or dimethylsulfoxide to prepare a sample, which was incubated at 37°C for 30min. Absorbance at 340nm was measured by an absorptiometer, and Inhibitory Rate was calculated by the equation as described below to determine IC 50 , the concentration of a test compound required to achieve 50% of inhibitory rate. Absorbance at 340nm of the compound was previously measured. Inhibitory Rate(%)= [1 - ( T -C min )/(C max -C min )]×100 where T is absorbance of the incubated sample with a test compound, C max is absorbance of the incubated sample without the compound, and C min is the non-incubated sample without the compound. The IC 50 values are shown in the Table 1. Test compound (EXAMPLE No.) (µg/ml) Test compound (EXAMPLE No.) IC 50 (µg/ml) 1 1.2 15 1.85 2 36 21 4.7 3 38 22 1.9 4 1.4 23 1.20 6 39 24 1.15 7 5.1 25 1.55 8 (reference) 230 26 1.90 9 150 27 1.85 11 150 28 1.30 13 1.4 29 3.95 14 1.65 30 3.30 TEST EXAMPLE 2 Anti-tumor in vitro test using the A2780 (human ovarian cancer cell): A2780 cells that were suspended in a RPMI 1640 culture medium containing 10% calf serum, penicillin(50U/ml), and streptomycin (50µg/ml) were seeded in a 96 well flat microplate by 1000cells (0.2ml)/well, and cultured in a 5% carbon dioxide atmospheric incubator at 37°C for 1 day. The compounds of the present invention that were dissolved in dimethylsulfoxide and diluted with a RPMI 1640 containing 10% calf serum to prepare the samples, provided that dimethylsulfoxide was restricted to 0.2% and below in concentration. The Supernatant liquids of the above A2780 cell wells were removed by aspiration, and then each 0. 2ml of the prepared samples were added to the wells, which were incubated in a 5% carbon dioxide atmospheric incubator at 37°C for 3 days. After the incubation, each 0.01ml of MTT solutions(3-(4,5-dimethylthiazole -2-yl)-2,5-diphenyltetrazolium bromide, 5mg/ml) were added to the wells, which were incubated for another 2hrs. After the supernatant liquids in the wells were removed by aspiration, the formazans formed in the wells were dissolved in 0.1ml of dimethylsulfoxide, and absorbances at 540nm were measured by a microplate reader to determine indices of live cell counts in the wells. Inhibitory Rate was calculated by the equation as described below to determine IC 50 , the concentration of a test compound required to achieve 50% of inhibitory rate. Inhibitory Rate(%) = [(C - T)/C]×100 where T is absorbance in the well with a test compound and C is absorbance in the well without the compound. The IC 50 values are shown in the Table 2. Test compound (EXAMPLE No.) IC 50 (µg/ml) Test compound (EXAMPLE No.) IC 50 (µg/ml) 1 0.023 17 1.4 2 0.58 20 6.8 3 0.22 21 0.079 4 0.017 22 0.14 5 7.2 23 0.006 6 0.14 24 0.006 7 0.20 25 0.05 8 (reference) 6.7 26 0.034 9 13 27 0.034 11 0.68 28 0.013 12 9.7 29 0.14 13 0.010 30 0.16 14 0.036 31 0.30 15 0.025 32 0.62 TEST EXAMPLE 3 Prophylactic experiment of collagen-induced arthritis in mice: The suspension of M. tuberculosis H37RA in Freund incomplete adjuvant(2mg/ml) was mixed with 0.3% typeII collagen (extracted from bovine articular cartilage, Collagen Gijutsu Kensyu Kai) in equal amounts to form an emulsion, 0.1ml of which was injected subcutaneously into the base of the tail of mice to sensitize it. After twenty-one days, 0.3% type II collagen was diluted with physiological saline solution to the one sixth concentration of the solution, 0.2ml of which was injected intraperitoneally to sensitize secondarily. The mice that the first sensitizations caused to fall into arthritis were excluded from the test. The suspensions of the compounds(in the Example 13, 27, and 28)in 0.5% sodium carboxymethylcellulose (CMC-Na) were administered orally to the test group of mice once a day for 5 weeks from the day after the second sensitization. 0.5% CMC-Na, solutions were administered to the control group of mice to be compared with. Each group was composed of eight mice. Daily symptoms in the mice limbs were observed to determine stratified scores(0 to 4, hence maximum 16). Scores and their standards are as follows. 0: No symptom 1: Tumefaction or rubor in only one finger(or heel) 2: Tumefaction or rubor in two or above fingers(or heels) or in parts of fore (or hind) paw(s) 3: Tumefaction or rubor in the wholes of fore (or hind) paw(s) including joints 4: Ankylosis in the joints of finger(s)(or heel(s)) or fore (or hind) paw(s) The results on the last day of this test are shown in the Table 3. Test compound (EXAMPLE No.) Dose mg/kg Averaged score Control 0 8.5±1.7 13 25 2.3±0.8* 13 50 0.4±0.4 27 50 1.7±1.1 28 50 3.0±1.1* Compared with the control group, the test groups of the compounds of the present invention show a significant prophylactic effect in a collagen-induced arthritis model in mice which is an animal model for rheumatoid arthritis. Furthermore, blood tests(blood cell count, GOT) and histological observations of main organs executed on the last day suggested that the compounds gave little toxicity on bone marrow, liver, heart, lung, spleen, pancreas, and gastrointestine. INDUSTRIAL APPLICABILITY The compounds of the present invention are confirmed to have tubulin polymerization inhibitory activity and anti-tumor effect. The prophylactic experiment of collagen-induced arthritis in mice which is an animal model for rheumatoid arthritis confirms them to have excellent anti-rheumatic effect. Furthermore, they have low toxicity and 5 weeks' continuous administration as executed in the Test Example did not lead to death. Blood tests and histological observations suggest that the compounds give little toxicity on bone marrow, liver, heart, lung, spleen, pancreas, and gastrointestine. Therefore, the compounds of the present invention are useful as low toxic anti-tumor agents and preventives or remedies for rheumatism.

Claims: Sulfonamide derivatives represented by the general formula (1) [wherein R 1 represents a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a nitro group, a hydroxy group, a cyano group, a C 1 to C 8 acyl group, an optionally substituted phenoxy group, or an optionally substituted amino group; R 2 represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a nitro group, a hydroxy group, a cyano group, a C 1 to C 8 acyl group, an optionally substituted phenoxy group,or an optionally substituted amino group; R 3 , R 4 may be the same or different and each independently represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a nitro group, a hydroxy group, a group as shown by the general formula(2) described below: ―(CH 2 ) n ―CO―R 7 (wherein R 7 represents a hydrogen atom, a hydroxy group, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, or an optionally substituted amino group, and n means an integer of 1-5), a group as shown by the general formula(3) described below: ― (CH 2 ) n ― B (wherein B represents an imidazolyl group, a triazolyl group, a tetrazolyl group, or an optionally substituted amino group, and n means any integer of 1-5), a group as shown by the general formula(4) described below: (wherein R 8 represents a C 1 -C 6 alkyl group, a C 1 to C 5 alkyl group substituted by 1 or 2 hydroxy group(s), a C 1 to C 5 alkyl group substituted by a C 1 to C 5 alkoxycarbonyl group, a C 1 to C 5 acyl group, or a pyridyl group; R 9 represents a C 1 -C 6 alkyl group or a hydroxy group; a and n means any integer of 0-3 and 0-6 respectively), a group as shown by the general formula(5) described below: (wherein R 9 represents a C 1 -C 6 alkyl group or a hydroxy group; b and n means any integer of 0-3 and 0-6 respectively), a group as shown by the general formula(6) described below: (wherein R 9 represents a C 1 -C 6 alkyl group or a hydroxy group; c and n means any integer of 0-3 and 0-6 respectively; Q represents an oxygen atom, a sulfur atom, or a group as shown by the general formula(7) described below: {wherein d means 1 or 2 }), a group as shown by the general formula(8) described below: ―(CH 2 ) n ―NR 10 R 11 (wherein R 10 , R 11 may be the same or different and each independently represents a hydrogen atom, a C 1 -C 6 alkyl group or an optionally substituted amino C 1 -C 6 alkyl group; n means any integer of 0-6 ),a group as shown by the general formula(9) described below: ―(CH 2 ) n ―S(O) e ―R 12 (wherein R 12 represents a hydrogen atom, a C 1 -C 6 alkyl group or an aryl group, an aralkyl group or an optionally substituted amino group; e and n means any integer of 0-3 and 0-6 respectively),or a group as shown by the general formula(10) described below: ―(CH 2 ) n ―OR 13 (wherein R 13 represents a hydrogen atom, a C 1 -C 6 alkyl group or an acyl group, a phosphate group or an optionally substituted aminoalkyl group; and n means any integer of 1-6 ), R 5 , R 6 may be the same or different and each independently represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, an acyl group, or an optionally substituted amino group; A represents any group of (1)an optionally substituted 5-membered heterocyclic group (except triazolyl group)whose ring members include at least 1 nitrogen atom and may include any atom(s) selected from the group consisting nitrogen atom, oxygen atom, and sulfur atom,(2)an optionally substituted alicyclic group, and (3)an alicyclic group whose ring members include at least 1 nitrogen atom and may include any atom(s) selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom], and the pharmaceutically acceptable salts thereof. Sulfonamide derivatives as defined in claim 1, wherein R 1 is a C 1 -C 6 alkoxy group, and R 2 , R 3 , R 4 , R 5 , and R 6 may be the same or different and each independently represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, or an optionally substituted amino group, or the pharmaceutically acceptable salts thereof. Sulfonamide derivatives as defined in claim 1, wherein R 1 is a C 1 -C 6 alkoxy group, and R 2 , R 3 , R 4 , R 5 ,and R 6 may be the same or different and each independently represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, or an optionally substituted amino group, and A represents an optionally substituted 5-membered heterocyclic group (except triazolyl group)whose ring members include at least 1 nitrogen atom and may include any atom(s) selected from the group consisting nitrogen atom, oxygen atom, and sulfur atom, or the pharmaceutically acceptable salts thereof. Sulfonamide derivatives as defined in any one of claims 1 - 3, wherein A represents an optionally substituted isoxazolyl group, or the pharmaceutically acceptable salts thereof. Sulfonamide derivatives as defined in claim 4, wherein A represents a 4-isoxazolyl group which has at least one C 1 -C 6 alkyl group at the 3- and 5- position, or the pharmaceutically acceptable salts thereof. Sulfonamide derivatives as defined in claim 4, wherein R 1 is a R 1 is a hydrogen atom or alkoxy group which is located at the para-position, and R 2 to R 6 are hydrogen atoms, or the pharmaceutically acceptable salts thereof. A pharmaceutical composition containing as an active ingredient sulfonamide derivatives( including case that R 1 is a hydrogen atom or A represents a triazolyl group in the general formula(1)) as defined in any one of claims 1 - 6, or the pharmaceutically acceptable salts thereof. A tubulin polymerization inhibitory agent containing as an active ingredient the sulfonamide derivatives (including the case that R 1 is a hydrogen atom or A is triazolyl group in the general formula(1)) as defined in any one of claims 1 - 6, or the pharmaceutically acceptable salts thereof. An anticancer agent containing as an active ingredient the sulfonamide derivatives ( including the case that R 1 is a hydrogen atom or A is triazolyl group in the general formula(1)) as defined in any one of claims 1 - 6, or the pharmaceutically acceptable salts thereof. A drug as a preventive or a remedy for rheumatism containing as an active ingredient the sulfonamide derivatives( including the case that R 1 is a hydrogen atom or A is triazolyl group in the general formula(1)) as defined in any one of claims 1 - 6, or the pharmaceutically acceptable salts thereof. A drug as a preventive or a remedy for rheumatism as defined in claim 10, wherein rheumatism is inflammatory rheumatism.

Inventors: MOROHASHI HIROHISA, SATO HIROSHI, MOROHASHI, HIROHISA, SATO, HIROSHI
Applicants: NIPPON KAYAKU KK, NIPPON KAYAKU KABUSHIKI KAISHA
Application year: 1998
Main classification: C07C311
IPC codes: C07D261, C07D211, C07D275, C07D231, C07D233, C07D277, C07D207, C07C311