TECHNICAL FIELD 0001 The present invention relates to novel benzylidene derivatives, and an antirheumatic agent, an osteoclast formation inhibiting agent, a nitrogen monoxide production inhibiting agent, and a transcription factor NFB suppressing agent comprising said benzylidene derivative as an active ingredient. The present invention further relates to a method for the prevention and/or treatment of rheumatic diseases, a method for the inhibition of osteoclast formation, a method for the inhibition of nitrogen monoxide production, and a method for the suppression of transcription factor NFB.

BACKGROUND ART 0002 Rheumatic disease is a systemic inflammatory disease involving a functional abnormality accompanied by swellings and pains in arthrosis as the primary symptom. The number of the patients in Japan is estimated as more than about 600 thousands (morbidity: about 0.5% of the Japanese population), and many of these patients are females of middle to advanced age. Although the development of this disease has not yet been well elucidated, it is believed to be a trigger for this disease that an immunological abnormality occurs for some reason, the autoimmune response is accelerated, and an activated macrophage, neutrophil, T-cell and the like are infiltrated to inflammatory focus. Then, these cells receive an inflammatory stimulus to produce various inflammatory mediators such as IL-1, IL-6, THF-, nitrogen monoxide (NO) and prostaglandin E2 (PGE2). The mediators then induce a cell adhesion factor, collagenase, protease and the like, which cause swelling and pain and accelerate the destruction of articular cartilage and bone. 0003 According to the recent findings, activation of NFB due to inflammatory stimulation induces cyclooxygenase-2 (COX-2) and inductive nitrogen monoxide synthase (i-NOS), and also accelerates an expression of cytokines. Cytokines and NO produced in the inflammatory focus activate NFB. As a result, it is believed that the production of inflammatory mediators is enhanced in the inflammatory focus and the chronic inflammation pathology accompanied by the tissue destruction is thus developed. NO is also associated with the activation of COX-2 and accelerates production of PGE2. 0004 Certain benzylidene compounds exhibit an anti-inflammatory effect, and therefore, they are currently used in the treatment of rheumatic diseases as a nonsteroidal anti-inflammatory drug (NSAID), for the purpose of suppressing pains and swellings. However, the use of such nonsteroidal anti-inflammatory drug is a mere symptomatic therapy for the suppression of pains and swellings due to rheumatic diseases and is not curable for the disease itself. 0005 On the other hand, antirheumatic agents (disease-modifying antirheumatic drug) inhibit the progression of rheumatic pathology and they are used in a radical therapy for the disease. The compounds of the present invention have been found to inhibit articular bone destruction, a rheumatic pathology, in a rheumatic model animal (NZB/KN) to which a nonsteroidal anti-inflammatory drug is not effective. Thus, the compounds have been found to be effective in a radical therapy of rheumatic diseases via a different mechanism from that of anti-inflammatory agents. 0006 Combination use of a disease-modifying antirheumatic drug (DMARD) such as immunosuppressants or immunomodulators and a nonsteroidal anti-inflammatory drug (NSAID) is often conducted in the treatment of chronic arthritis such as rheumatoid arthritis. However, these drug have drawbacks in that the former may often cause serious side effects such as blood disorder, and the latter may cause gastrointestinal disorder due to prolonged administration. Accordingly, a drug which possesses the DMARD and NSAID effects but less side effects would be very useful as a therapeutic agent for rheumatoid arthritis.

SUMMARY OF THE INVENTION 0007 The present inventors have found that particular benzylidene derivatives, i.e. the compounds of formula I: 2

0008 wherein 0009 R1 is hydrogen, lower alkyl, lower alkoxy, hydroxy lower alkyl, or carboxy lower alkyl and R4 is hydroxy; or 0010 R1 and R4 taken together form CR5R6 (CH2)mO or CR5R6(CH2)pCH(OH)O0011 wherein m is an integer of 1 to 3; 0012 p is an integer of 0 to 2; and 0013 R5 and R6 are each independently hydrogen, lower alkyl, lower alkoxy, or hydroxy lower alkyl; 0014 R2 is hydrogen, lower alkyl, lower alkoxy, hydroxy lower alkyl, or carboxy lower alkyl; and 0015 R3 is hydrogen, lower alkyl, cycloalkyl, lower alkoxy, arylalkyloxy, heteroarylalkyloxy, lower alkylcarbonyl, arylcarbonyl, substituted or unsubstituted carbamoyl or the group represented by the formula:

(CH2)n-Q

0016 wherein Q is hydroxy, substituted or unsubstituted amino, aryl, heteroaryl, hydroxycarbonyl or lower alkyloxycarbonyl; and 0017 n is an integer of 0 to 3 0018 exhibit not only anti-inflammatory effect but also antirheumatic effect. The present invention has been accomplished on the basis of the above finding. 0019 The present inventors also have found that the above compounds inhibit enhanced formation of osteoclast caused by PGE2. 0020 Also, the above compounds have been found to suppress an inducible nitrogen monoxide synthase (i-NOS) to inhibit NO production. 0021 Further, the above compounds have been found to posses suppressive activity on a transcription factor NFB. 0022 Accordingly, the present invention provides novel uses of such derivatives as an antirheumatic agent, an osteoclast formation inhibiting agent, a nitrogen monoxide production inhibiting agent, and a transcription factor NFB suppressing agent. 0023 Thus, the present invention provides an antirheumatic agent comprising a compound of formula I or pharmaceutically acceptable salt or hydrate thereof as an active ingredient. 0024 The present invention also provides an osteoclast formation inhibiting agent comprising a compound of formula I or pharmaceutically acceptable salt or hydrate thereof as an active ingredient. 0025 The present invention further provides a nitrogen monoxide production inhibiting agent comprising a compound of formula I or pharmaceutically acceptable salt or hydrate thereof as an active ingredient. 0026 The present invention yet further provides a transcription factor NFB suppressing agent comprising a compound of formula I or pharmaceutically acceptable salt or hydrate thereof as an active ingredient. 0027 The compounds of the formula I wherein R1 and R2 are both t-butyl, more preferably R1 and R2 are both t-butyl and R4 is hydroxy, more preferably R1 and R2 are both t-butyl, R3 is lower alkyl and R4 is hydroxy, much more preferably R1 and R2 are both t-butyl, R3 is ethyl and R4 is hydroxy, are preferred antirheumatic agents, osteoclast formation inhibiting agents, nitrogen monoxide production inhibiting agents and transcription factor NFB suppressing agents. 0028 The present invention further provides use of the compounds of formula I for the manufacture of anti-rheumatic agent. 0029 Also, the present invention provides use of the compounds of formula I for the manufacture of osteoclast formation inhibiting agent. 0030 Further, the present invention provides use of the compounds of formula I for the manufacture of nitrogen monoxide production inhibiting agent. 0031 Yet further, the present invention provides use of the compounds of formula I for the manufacture of transcription factor NFB suppressing agent. 0032 The present invention further provides a method for the prevention and/or treatment of rheumatoid arthritis which comprises administering an effective amount of a compound of formula I to mammals in need thereof. 0033 Also, the present invention provides a method for the inhibition of osteoclast formation which comprises administering an effective amount of a compound of formula I to mammals in need thereof. 0034 Further, the present invention provides a method for the inhibition of nitrogen monoxide production which comprises administering an effective amount of a compound of formula I to mammals in need thereof. 0035 Yet further, the present invention provides a method for the suppression of transcription factor NFB which comprises administering an effective amount of a compound of formula I to mammals in need thereof. 0036 Among the compounds represented by the above formula I, some compounds have been disclosed as inhibiting agent against PGE2 production in Japanese Patent Publication No. 211819/1994 (published on Aug. 2, 1994). 0037 The present invention further provides novel compounds of formula I: 3

0038 wherein 0039 R1 is hydroxy lower alkyl or carboxy lower alkyl and R4 is hydroxy; or 0040 R1 and R4 taken together form CR5R6(CH2)mO or CR5R6(CH2)pCH(OH)O0041 wherein m is an integer of 1 to 3; 0042 p is an integer of 0 to 2; and 0043 R5 and R6 are each independently hydrogen, lower alkyl, lower alkoxy, or hydroxy lower alkyl; 0044 R2 is hydrogen, lower alkyl, lower alkoxy, hydroxy lower alkyl, or carboxy lower alkyl; and 0045 R3 is hydrogen, lower alkyl, cycloalkyl, lower alkoxy, arylalkyloxy, heteroarylalkyloxy, lower alkylcarbonyl, arylcarbonyl, substituted or unsubstituted carbamoyl or the group represented by the formula:

(CH2)n-Q

0046 wherein Q is hydroxy, substituted or unsubstituted amino, aryl, heteroaryl, hydroxycarbonyl or lower alkyloxycarbonyl; and 0047 n is an integer of 0 to 3 0048 or pharmaceutically acceptable salt or hydrate thereof.

BRIEF DESCRIPTION OF THE DRAWINGS 0049 FIG. 1 is a graph showing the inhibitory effect of the compound of the invention against adjuvant articular swelling. Values in the graph are mean of the eight independent experiments, and significance test was performed according to Dunnett's t-test (*p<0.05, **p<0.01: vs. vehicle group). 0050 FIG. 2 is a X-ray observation score for bone destruction in arthrosis. 0051 FIG. 3 is a graph showing the inhibitory effect against the destruction of articular bone in adjuvant arthritis. Values in the graph are meanstandard error of eight independent experiments, and significance test was performed according to Dunnett's t-test (*p<0.05, **p<0.01: vs. vehicle group). 0052 FIG. 4 is a graph showing the repressive effect on the IL-6 level in articular tissue. Nor: normal rat, Veh: vehicle, Buc: Bucillamine, CsA: Cyclosporin A. Values in the graph are meanstandard error of seven independent experiments, and significance test was performed according to Dunnett's t-test (p<0.01: vs. normal group, **p<0.01: vs. vehicle group). 0053 FIG. 5 is a graph showing the inhibitory effect against bone destruction in NZB/KN mouse. Veh: vehicle, CsA: Cyclosporin A, Ind: Indomethacin, Ten: Tenidap. N refers to the number of animals tested. Values in the graph are meanstandard error, and significance test was performed according to Dunnett's t-test (*p<0.05, **p<0.01: vs. vehicle group). 0054 FIG. 6 is a graph showing the repressive effect on MRL/l mouse blood acute phase protein SAP. Veh: vehicle, Buc: Bucillamine, Lob: Lobenzarit, Ten: Tenidap, Ind: Indomethacin, and Pred: Predonisolone. Values in the graph are meanstandard error, and significance test was performed according to Dunnett's t-test (*p<0.05, **p<0.01: vs. vehicle group). 0055 FIG. 7 is a graph showing the repressive effect on suppressive effect on blood NOx level in adjuvant arthritis rat. Nor: normal rat, Veh: vehicle, Ind: Indomethacin, and Dex: Dexamethazon. Values in the graph are meanstandard error of eight independent experiments, and significance test was performed according to Dunnett's t-test (p<0.01: vs. normal group, *p<0.05, **p<0.01: vs. vehicle group).

DETAILED DESCRIPTION 0056 As is apparent from the above formula, the compounds of the invention of formula I can exist in the stereostructures of (E)-type. Accordingly, unless otherwise noted, the compound I described in this specification should be construed to include (E)-isomer. 0057 For purposes of the present invention, as disclosed and claimed herein, the following terms are defined as below. 0058 The term lower alkyl means straight or branched C1-C8 alkyl and examples thereof include methyl, ethyl, n-propyl, i-propyl n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, s-pentyl, t-pentyl, n-hexyl, neohexyl, i-hexyl, s-hexyl, t-hexyl, heptyl and octyl. Among them, a straight or branched C1-C4 alkyl is preferred. The most preferred one is methyl or ethyl. 0059 The term lower alkoxy means straight or branched C1-C6 alkyloxy and examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, neopentyloxy, s-pentyloxy, t-pentyloxy, n-hexyloxy, neohexyloxy, i-hexyloxy, s-hexyloxy and t-hexyloxy and the like. Among them, a C1-C3 alkoxy group is preferred. The most preferred one is methoxy. 0060 The term hydroxy lower alkyl means a group formed by substituting the lower alkyl group defined above with hydroxy group(s). Specific examples thereof include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl and the like. 0061 The term carboxy lower alkyl means a group formed by substituting the lower alkyl group defined above with carboxy group(s). Examples thereof include carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, 1,1-dimethyl-2-carboxyethyl and the like. 0062 The term cycloalkyl means C3-C7 cycloalkyl and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Among them, C3-C5 cycloalkyl is preferred. 0063 The term aryl means unsubstituted or substituted phenyl or naphthyl and may be substituted by one or more substituents including halogen, lower alkoxy, lower alkyl, nitro and the like. Examples of aryl include phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-nitrophenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 3,4-dinitrophenyl, 1-naphtyl, 2-naphtyl and the like. 0064 The term arylalkyloxy means a group formed by substituting a lower alkoxy group with an aryl group(s) as defined above and examples thereof include benzyloxy, 4-chlorobenzyloxy, 4-methoxybenzyloxy, 3,4-dichlorobenzyloxy, 3,4-dimethoxybenzyloxy, 4-nitrobenzyloxy, 2-phenylethyloxy, 2-(4-chlorophenyl)ethyloxy, 2-(4-methoxyphenyl)ethyloxy, 1-naphtylmethyloxy, 2-naphtylmethyloxy and the like. Among them, benzyloxy is preferred. 0065 The term heteroaryl means a group containing 1-4 hetero atoms and examples thereof include pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl and tetrazolyl. For purposes of the present invention, pyridyl, thiazolyl, oxazolyl and imidazolyl are preferred and pyridyl is most preferred. 0066 The term heteroarylalkyloxy means a group formed by substituting an alkoxy group with a heteroaryl group(s) as defined above and examples thereof include 2-pyridylmethyloxy, 3-pyridylmethyloxy, 4-pyridylmethyloxy, 2-imidazolylmethyloxy, 4-imidazolylmethyloxy, 2-thiazolylmethyloxy, 4-thiazolylmethyloxy and the like. 0067 Examples of lower alkylcarbonyl include acetyl, propionyl, butyryl, valeroyl, hexanoyl, heptanoyl and octanoyl. 0068 Examples of arylcarbonyl include benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl, 3,4-dichlorobenzoyl, 3,4-dimethoxybenzoyl, 3,4-dinitrobenzoyl, 1-naphthoyl, 2-naphthoyl and the like. 0069 For the term substituted or unsubstituted carbamoyl, examples of the substituent therefor include lower alkyl, lower alkoxy, hydroxy, cycloalkyl, arylalkyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, cycloalkyloxy and arylalkyloxy, and one or more of these substituents may be substituted at the nitrogen atom. Among them, lower alkyl, lower alkoxy and hydroxy are preferred. Examples of substituted carbamoyl include N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-hydroxycarbamoyl, N-methyl-N-hydroxycarbamoyl, N-methoxycarbamoyl, N-methoxy-N-methylcarbamoyl, N-ethylcarbamoyl, N,N-diethylcarbamoyl, N-ethyl-N-hydroxycarbamoyl, N-propylcarbamoyl, N,N-dipropylcarbamoyl and N-propyl-N-hydroxycarbamoyl. 0070 Examples of halogen include fluorine, chlorine, bromine and iodine. 0071 Examples of lower alkyloxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl and the like. 0072 The term substituted amino means mono- or di-substituted amino, and examples of substituent include lower alkyl and arylalkyl as defined above. 0073 The term pharmaceutically acceptable salt or hydrate refers to salts or hydrates of the compounds represented by the formula I which are non-toxic to a living thing. Typical pharmaceutically acceptable salts include inorganic or organic salts formed by the reaction of a compound of formula I with an inorganic or organic acid or base. Such salts are known as acid or base addition salts. 0074 Examples of commonly used acids to form acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like, and organic acids such as p-toluene sulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. 0075 Example of commonly used bases to form base addition salts include inorganic bases such as ammonium hydroxide, ammonium carbonate, ammonium hydrogen carbonate, alkaline metal or alkaline earth metal hydroxides or carbonates and the like, and organic bases such as aliphatic amines, primary, secondary and tertiary amines, and aliphatic diamines and the like. 0076 In general, the above pharmaceutically acceptable acid or base addition salts can be obtained by the reaction of a compound of formula I with equimolar or excess amount of an acid or base. 0077 The compound of the invention can be essentially prepared by the process described in the Japanese Patent Publication No. 211819/1994, the disclosure of which is herein incorporated by reference. However, the present invention is by no means limited by the process per se. One process for the production of the compounds of the invention is exemplified in the following Preparations. 4

0078 In the above formulae, R1, R2, and R3 are as defined above and R7 is hydrogen or a hydroxy-protecting group. 0079 In the case that R7 of the compound 6 is a hydroxy-protecting group, examples of the protecting group include methoxymethyl, methoxyethyl, trimethylsilyl, tert-butyldimethylsilyl. R7 is preferably a hydroxy-protecting group, particularly methoxymethyl group. 0080 One of the starting compounds for the above reaction, the sulfur-containing compound 4 can be prepared, for example, according to a reaction scheme below. 5

0081 In the above formulae, R3 is as defined above. 0082 3-Chloropropylsulfonyl chloride 1 is reacted with amine 2 to yield sulfonamide intermediate 3. 0083 The reaction is carried out in the presence of base (A), if necessary, in a solvent such as ether, chloroform, methylene chloride, dichloroethane, tetrahydrofuran, dimethoxyethane, diethoxyethane, benzene, toluene, xylene, ethyl acetate, methyl acetate and the like, which solvent may contain water. The amine (R3NH2) may be in the form of hydrochloride salt. 0084 The base (A) used in the case of necessity includes alkali metal bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium hydrogencarbonate and the like, and organic bases such as pyridine, 4-N,N-dimethylaminopyridine (DMAP), triethylamine, diisobutyl ethylamine, 1,8-diazabicyclo5,4,0undec-7-ene (DBU), 1,4-diazabicyclo2,2,2octane (DABCO) and the like. When an alkali metal base is used, it is preferable to add a phase transfer catalyst, if necessary. Examples of preferred phase transfer catalysts are quaternary ammonium salts such as N-benzyltrimethylammonium salts, tetrabutylammonium salts and the like. 0085 The reaction for converting sulfonamide intermediate 3 into sulfur-containing heterocyclic compound 4 can be carried out in the presence of a base (B) in a solvent as described above, while anhydrous solvents such as dimethyl sulfoxide, dimethylformamide and the like may also be used and rather preferable. Sodium hydride and lithium hydride can be used as a base B as well as those described above. 0086 Alternatively, sulfur-containing compound 4 can be prepared directly from compound 1 without separation of sulfonamide intermediate 3. In this case, the reaction of compound 1 with amine 2 is carried out in a suitable solvent in the presence of two equivalents of a base. The solvent and the base may be selected from those exemplified above but it is particularly preferable to use sodium hydride as a base and dimethylformamide as a solvent. 6

0087 Alternatively, the desired sulfur-containing compound 4 can also be obtained from commercially available -sultone 5. (See Preparation). Briefly, compound 5 is allowed to react with amine (R3NH2) and the resultant product is then treated with a dehydrating agent. The reaction can be carried out without solvent but may be conducted in a solvent described above, if necessary. Commonly used reagent such as phosphorus oxychloride, thionyl chloride, phosphorus pentachloride, phosphorus pentoxide and the like may be used as a dehydrating agent, and phosphorus oxychloride is particularly preferable. 0088 The aldol reaction between compounds 6 and 4 obtained above is carried out in the presence of a base (C) in a suitable solvent. Examples of base (C) include organic lithium salts such as n-butyllithium, sec-butyllithium, tert-butyllithium, phenyllithium, lithium diisopropylamide, lithium diethylamide, lithium hexamethyldisilazane and the like, and alkali metal bases such as sodium hydride and potassium tert-butoxide and the like. Particularly, lithium diisopropylamide or lithium hexamethyldisilazane is preferable. 0089 Examples of reaction solvents include ether solvents such as diethyl ether, tetrahydrofuran (THF), dimethoxyethane, diethoxyethane and the like or hydrocarbon solvents such as n-hexane, cyclohexane and the like. The reaction is preferably conducted in the presence of a reagent that serves as a ligand of lithium metal, for example tetramethylethylenediamine, hexamethylphosphoramide and the like, if necessary. 0090 The reaction is carried out at temperature ranging from 80 C. to 50 C. with preference in lower temperature range. 0091 Aldol adduct 7 is converted to compound I in the presence of an acid. Examples of acids include organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like and inorganic acids such as sulfuric acid, hydrochloric acid and the like. Further, ordinary dehydrating agents such as thionyl chloride, methanesulfonyl chloride, aluminium chloride, phosphorus oxychloride, phosphorus pentachloride and the like can be used. Preferably, the reaction is carried out with heating in an aromatic hydrocarbon such as benzene, toluene, xylene and the like, a halogenated hydrocarbon such as chloroform, dichloromethane, dichloroethane and the like, or an ether solvent such as tetrahydrofuran, dimethoxyethane, diethoxyethane and the like. 7

0092 Base (C) in the above formula is as defined above. Y means an N-protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 4-nitrobenzyl and the like. The reaction conditions of the aldol reaction are similar to those described in the reaction scheme I above. Dehydrating and deprotecting reagents used in the conversion of aldol adduct 7 to compounds 10 include p-toluenesulfonic acid and trifluoroacetic acid, aluminium chloride, titanium tetrachloride and the like. The conditions such as reaction solvent, temperature and the like are similar to those described in reaction scheme I. Compound 8 is deprotected to obtain compound 10, which is the compound of formula I wherein R3 is hydrogen. 8

0093 In this reaction, a desired substituent R3 is added to compound 10 obtained in the above reaction scheme II, which corresponds to the compound of formula I wherein R3 is hydrogen in the formula I, to yield various derivatives. Base (D) to be used when R3X is an alkylating agent includes alkali metal salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen carbonate, lithium hydroxide and the like, or organic bases such as pyridine, triethylamine, diisopropylethylamine and the like. The alkylation is preferably carried out using sodium hydroxide or potassium carbonate in the presence of an appropriate quaternary ammonium salt as a phase transfer catalyst. 0094 In the case where R3X is an acylating agent, an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine or the like is preferably used as base (D). 0095 When R3X is a carbamoylating agent or alkoxycarbonylating agent, an organic lithium base such as n-butyllithium, lithium hexamethyldisilazane, lithium diisopropylamide or the like is preferably utilized as base (D). The present invention is not limited to the use of these bases, and organic bases such as pyridine, triethylamine, diisopropylethylamine and the like or the alkali metal bases described above are also useable. 9

0096 Compounds 12, which corresponds to the compound of formula I wherein R3 is OH, is obtained by de-benzylation of compounds 11. The de-benzylation is carried out using a deprotecting agent. The deprotection is conducted by hydrogenation in the presence of palladium on carbon or platinum oxide as catalyst, or by using a Lewis acid such as aluminium chloride, titanium tetrachloride or the like along with anisole, 2,6-di-tert-butylphenol and the like, if necessary. 0097 Besides halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like, nitromethane, benzene, toluene, xylene and the like can also be used as a reaction solvent. 0098 The processes in the above schemes I, II and III are generally applicable to the production of compounds I of the invention, and they are specifically illustrated in Preparations 1-43 below. 0099 The compound I of the present invention can be orally or parenterally administered as an anti-inflammatory agent. In the case of oral administration, a compound of the present invention may be formulated into ordinary formulations in the form of solid formulations such as tablets, powders, granules, capsules and the like; solutions; oily suspensions; or liquid formulations such as syrups, elixirs and the like. In the case of parenteral administration, a compound of the present invention may be formulated into an aqueous or oily suspension for injection or an external preparation. In preparing the formulations, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents or the like may be used, and other additives, such as preservatives, stabilizers or the like may also be included. 0100 Although appropriate daily dosage of the compound of the invention varies depending upon the administration route, age, body weight and conditions of a particular patient, and the kind of disease to be treated. In general, however, in the case of adult patients, it may be between 10-500 mg, preferably 50-100 mg for oral administration, and 1-250 mg, preferably 5-10 mg for parenteral administration, in 1-5 divisions. 0101 The following Preparations and Examples are provided to further illustrate the present invention and are not to be construed as limiting thereof. The abbreviations used in the Preparations and Examples have the following meanings: 0102 LDA: lithium diisopropylamide; 0103 MOM: methoxymethyl; 0104 p-TsOH: p-toluenesulfonic acid; 0105 THF: tetrahydrofuran; 0106 DMF: N,N-Dimethylformamide; 0107 HMPA: hexamethylphosphoramide; 0108 LiHMDS: lithium hexamethyldisilazane; 0109 DBU: 1,8-diazabicyclo5,4,0undec-7-ene; and 0110 DIBAL: diisobutylalminium hydride. 10

0111 Preparation 1 (R3Et) 0112 N-Ethyl-1,2-isothiazolidine-1,1-dioxide (4a) 0113 To a solution of 3-chloropropylsulfonyl chloride 1 (6.1 g, 34.5 mmol) in ether (25 ml) was dropwise added ethylamine (a 70% aqueous solution, 4.4 g, 68.3 mmol) with stirring and ice-cooling over 15 minutes, and the resultant mixture was stirred for one hour at room temperature. The reaction mixture was concentrated in vacuo, Benzene (100 ml) was added to the residue, and the solvent was removed in vacuo. To the residue was added ether (150 ml) and filtered to remove the insoluble material. The filtrate was distilled in vacuo to remove ether and 6.96 g (yield, about 100%) of crude N-ethyl-3-chloro propylsulfonamide (intermediate 3a) was obtained as colorless crystals (m.p.30-32 C.). To a solution of this intermediate 3a (6.96 g, 34.5 mmol) in THF (50 ml) was slowly added sodium hydride (60% in oil, 1.52 g, 38.0 mmol) with stirring under ice-cooling over 15 minutes. The reaction mixture was stirred for another 30 minutes at room temperature. After the addition of ether (50 ml), the mixture was filtered to remove insoluble material and the solvent was distilled in vacuo to give 4.93 g (96%) of the desired compound 4a as a pale yellow oil. IR (CHCl3)cm1: 3018, 2976, 2868, 1452, 1306, 1220, 1179, 1129, 1015; NMR (CDCl3) : 1.24 (3H, t, J7.4 Hz, CH3), 2.28-2.42 (2H, m, CH2), 3.10 (2H, q, J7.4 z, CH2), 3.15 (2H, t, J7.6 Hz, CH2), 3.22-3.29 (2H, m, CH2). 0114 Preparation 2 (R3Me) 0115 N-Methyl-1,2-isothiazolidine-1,1-dioxide (4b) 0116 3-Chloropropylsulfonyl chloride 1 (16.8 g, 94.9 mmol), ethylamine hydrochloride (13.5 g, 200 mmol), and potassium carbonate (27.6 g, 200 mmol) were sequentially added to ethyl acetate (500 ml). After the addition of N-benzyltrimethylammonium chloride (about 200 mg) to the mixture, the resultant mixture was stirred for 2 hours at room temperature and dried over anhydrous sodium sulfate. The mixture was filtered through a small amount of silica gel and the filtrate was concentrated in vacuo to give 12 g (74%) of crude N-methyl-3-chloropropylsulfonamide (intermediate 3b) as a pale yellow oil. 0117 To a solution of said intermediate 3b (11.79 g, 68.69 mmol) in benzene (300 ml) was added DBU (10.79 ml, 72.12 mmol), and the resultant mixture was stirred for 24 hours at room temperature and filtered through a small amount of silica gel. The solvent was removed to give 7.0 g (75%) of the desired compound 4b as a colorless solid (m.p.36-40 C.). IR (CHCl3)cm1: 3016, 1451, 1307, 1218, 1187, 1127; NMR (CDCl3) : 2.27-2.42 (2H, m, CH2), 2.69 (3H, s, CH3), 3.11-3.20 (2H, m, CH2), 3.22 (2H, t, J6.Hz, CH2) 0118 Preparation 3 (R3CH2CH(CH3)2) 0119 N-Isobutyl-1,2-isothiazolidine-1,1-dioxide (4c) 0120 3-Chloropropylsulfonyl chloride 1 (7.08 g, 40 mmol), isobutylamine (7.3 g, 100 mmol) and sodium bicarbonate (3.36 g, 40 mmol) were sequentially added to a mixture of ethyl acetate (200 ml) and water (20 ml). To the mixture was added N-benzyltrimethylammonium chloride (about 100 mg), and the resultant mixture was stirred for 3 hours at room temperature and then treated in a manner described in Preparation 2 to give 8.19 g (96%) of crude N-isobutyl-3-chloropropylsulfonamide (intermediate 3c) as colorless crystals (m.p.68-69 C.). 0121 To a solution of said intermediate 3c (4.27 g, 20 mmol) in benzene (60 ml) was added DBU (3.3 ml, 22 mmol), and the reaction mixture was treated in a manner as described in Preparation 2 to give 3.37 g (95%) of the desired compound 4c as a colorless oil. IR (CHCl3)cm1: 3016, 2956, 1465, 1304, 1226, 1131, 1024; NMR (CDCl3) : 0.95 (6H, d, J6.6 Hz, (CH3)2), 1.75-1.96 (1H, m, CH), 2.27-2.42 (2H, m, CH2), 2.80 (2H, d, J7.4 Hz, CH2), 3.10-3.19 (2H, m, CH2), 3.24 (2H, t, J6.8 Hz, CH2). 0122 Preparation 4 (R3Cyclopropyl) 0123 N-Cyclopropyl-1,2-isothiazolidine-1,1-dioxide (4d) 0124 3-chloropropylsulfonyl chloride 1 (7.08 g, 40 mmol), cyclopropylamine (6.0 g, 105 mmol) and sodium bicarbonate (3.7 g, 44 mmol) were treated in a mixture of ether (200 ml) and water (10 ml) in a manner as described in Preparation 3 to give 8.0 g (about 100%) of crude N-cyclopropyl-3-chloropropylsulfonamide (intermediate 3d) as crystals (m.p.48-49.5 C.). 0125 Said intermediate 3d (1.98 g, 10 mmol) was reacted with DBU (1.65 ml, 11 mmol) in benzene (30 ml) in a manner as described in Preparation 2 to give 1.40 g (87%) of the desired compound 4d as a pale yellow oil. IR (CHCl3)cm1: 3016, 1309, 1221, 1140, 1026; NMR (CDCl3) : 0.60-0.85 (4H, m, cyclopropyl), 2.20-2.40 (2H, m, CH2), 3.15-3.25 (3H, m, CH2CH), 3.32 (2H, t, J6.6 Hz, CH2). 0126 Preparation 5 (R3CH2CH2CH3) 0127 N-n-Propyl-1,2-isothiazolidine-1,1-dioxide (4e) 0128 3-chloropropylsulfonyl chloride 1 (7.08 g, 40 mmol), n-propylamine (5.90 g, 100 mmol), potassium carbonate (5.52 g, 40 mmol) and a small amount of N-benzyltrimethylammonium chloride (about 100 mg) were stirred in a mixture of ether (200 ml) and water (20 ml) for 3 hours, the reaction mixture was then treated in a manner as described in Preparation 2 to give 8.0 g (about 100%) of crude N-n-propyl-3-chloropropylsulfonamide (intermediate 3e) as crystals (m.p.47.5-48 C.). 0129 Said intermediate 3e (2.0 g, 10 mmol) was reacted with DUB (1.65 ml, 11 mmol) in benzene (30 ml) in a manner as described in Preparation 2 to give 1.41 g (86%) of the desired compound 4e as a pale yellow to colorless oil. IR (CHCl3)cm1: 3018, 2962, 2868, 1304, 1224, 1130, 1019; NMR (CDCl3) : 0.96 (3H, t, J7 Hz, CH3), 1.52-1.72 (2H, m, CH2), 2.28-2.42 (2H, m, CH2), 2.94-3.04 (2H, m, CH2), 3.10-3.20 (2H, m, CH2), 3.25 (2H, t, J6.7 Hz, CH2). 0130 Preparation 6 (R3OCH3) 0131 N-Methoxy-1,2-isothiazolidine-1,1-dioxide (4f) 0132 3-Chloropropylsulfonyl chloride 1 (7.08 g, 40 mmol), O-methylhydroxylamine hydrochloride (3.76 g, 40 mmol), and potassium carbonate (5.80 g, 42 mmol) were reacted in a manner as described in Preparation 5 to give 7.02 g (94%) of crude N-methoxy-3-chloropropylsulfonamide (intermediate 3f) as a colorless to pale yellow oil. 0133 The intermediate 3f (6.25 g, 33.3 mmol) was reacted with sodium hydride (60% in oil, 1.47 g, 36.7 mmol) in a manner as described in Preparation 1 to give 3.70 g (73%) of the desired compound 4f as a colorless oil. IR (CHCl3)cm1: 3022, 1355, 1249, 1222, 1165, 1138, 1035, 1011; NMR (CDCl3) : 2.37-2.50 (2H, m, CH2), 3.20-3.14 (2H, m, CH2), 3.50 (2H, t, J7.0 Hz, CH2), 3.81 (3H, s, OCH3). 0134 Preparation 7 (R3OCH2C6H5) 0135 N-Benzyloxy-1,2-isothiazolidine-1,1-dioxide (4 g) 0136 3-Chloropropylsulfonyl chloride 1 (30.28 g, 0.17 mol), O-benzylhydroxylamine hydrochloride (27.3 g, 0.17 mol), potassium carbonate (50 g, 0.36 mol) and tetrabutylammonium sulfate (about 500 mg) are reacted in a mixture of ether (1L) and water (100 ml) for 24 hours at room temperature and the reaction mixture was extracted with ethyl acetate. The extract was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of ethyl acetate/n-hexane (1:4), 18.4 g (41%) of crude N-benzyloxy-3-chloropropylsulfonamide (intermediate 3g) was obtained as a pale yellow oil. 0137 To a solution of the above intermediate 3g (18.4 g, 69.9 mmol) in THF (150 ml) was added sodium hydride (60% in oil, 2.94 g, 73.4 mmol) and the reaction was carried out in a manner as described in Preparation 1. The product was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of ethyl acetate/n-hexane (1:5), 10.75 g (68%) of the desired compound 4g was obtained as a colorless crystal. M.p.52-54 C. IR (CHCl3)cm1: 3022, 2956, 1453, 1354, 1165, 1140, 1081, 1000; NMR(CDCl3) : 2.30-2.48 (2H, m, CH2), 3.04-3.14 (2H, m, CH2), 3.45 (2H, t, J6.9 Hz, CH2), 5.00 (2H, s, OCH2), 7.30-7.45 (5H, m, C6H5). 0138 Preparation 8 (R34-methoxybenzyl) 0139 N-(4-Methoxybenzyl)-1,2-isothiazolidine-1,1-dioxide (4 h) 0140 3-Chloropropylsulfonyl chloride 1 (17.7 g, 0.1 mol), p-methoxybenzylamine (15.0 g, 0.11 mol), and sodium bicarbonate (8.4 g, 0.1 mol) were reacted in a mixture of ethyl acetate (400 ml) and water (40 ml) in a manner as described in Preparation 3 to give 19.1 g (69%) of crude N-(4-methoxybenzyl)-3-chloropropylsulfonamide (intermediate 3h) as colorless crystals. M.p.78-80 C. 0141 The above intermediate 3h (11.11 g, 40 mmol) was reacted with DBU (6.6 ml, 40 mmol) in benzene (150 ml). The resultant mixture was treated in a manner as described in Preparation 2 to give 8.89 g (92%) of the desired compound 4h as crystals. M.p.48-51 C. IR (CHCl3)cm1: 3016, 1612, 1511, 1304, 1245, 1136, 1034. NMR (CDCl3) : 2.20-2.38 (2H, m, CH2), 3.09 (2H, t, J6.8 Hz, CH2), 3.14-3.24 (2H, m, CH2), 3.81 (3H, s, OCH3), 4.12 (2H, s, CH2), 6.84-6.94 (2H, m, CH2), 7.22-7.32 (4H, m, 4aromatic-H). 0142 Preparation 9 (R33,4-dimethoxybenzyl) 0143 N-(3,4-Dimethoxybenzyl)-1,2-isothiazolidine-1,1-dioxide (4i) 0144 3-Chloropropylsulfonyl chloride 1 (8.85 g, 50 mmol), 3,4-dimethoxybenzylamine (9.0 ml, 60 mmol) and potassium carbonate (4.14 g, 30 mmol) were treated in a manner as described in Preparation 2 to give 14.5 g (94%) of crude N-(3,4-dimethoxybenzyl)-3-chloropropylsulfonamide (intermediate 3i). From the intermediate 3i, the desired compound 4i (yield: 69%) was yielded in a manner as described in Preparation 1. IR (CHCl3)cm1: 3018, 1516, 1307, 1262, 1225, 1155, 1138, 1027. NMR (CDCl3) : 2.22-2.38 (2H, m, CH2), 3.11 (2H, t, J6.7 Hz, CH2), 3.16-3.25 (2H, m, CH2), 3.88 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.12 (2H, s, CH2), 6.79-6.91 (3H, m, 3aromatic-H). 0145 Preparation 10 (R3C6H5) 0146 N-Phenyl-1,2-isothiazolidine-1,1-dioxide (4j) 0147 3-Chloropropylsulfonyl chloride 1 (1.456 g, 8.23 mmol) was dropwise added to a solution of aniline (0.5 ml, 8.23 mmol) in pyridine (5 ml) with cooling at 20 C. to 30 C. over about 5 minutes. After the completion of the addition, the reaction mixture was stirred for another 45 minutes at room temperature. The reaction mixture was concentrated in vacuo and the residue was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of ethyl acetate/n-hexane (1:2), 1.683 g (88%) of N-phenyl-3-chloropropylsulfonamide (intermediate 3j) was obtained as a yellow oil. From the intermediate 3j, the desired compound 4j (yield: 57%) was yielded as a pale yellow solid in a manner as described in Preparation 1. IR (CHCl3)cm1: 3020, 1598, 1495, 1315, 1139. NMR (CDCl3) : 2.46-2.60 (2H, m, CH2), 3.34-3.42 (2H, m, CH2), 3.78 (2H, t, J6.6 Hz, CH2), 7.10-7.40 (5H, m, C6H5). 0148 Preparation 11 (R34-chlorophenyl) 0149 N-(4-Chlorophenyl)-1,2-isothiazolidine-1,1-dioxide (4k) 0150 According to a similar method to that of Preparation 10, 3-chloropropylsulfonyl chloride was reacted with 4-chloroaniline in pyridine to give N-(4-chlorophenyl)-3-chloropropylsulfonamide (intermediate 3k) (yield 93%). From the intermediate 3k, the desired compound 4k (yield: 68%) was yielded as colorless crystals (m.p.110.5-111.5 C.) in a manner as described in Preparation 1. IR (KBr)cm1: 3010, 2960, 1595, 1493, 1300, 1267, 1131. NMR (CDCl3) : 2.47-2.61 (2H, m, CH2), 3.35-3.43 (2H, m, CH2), 3.76 (2H, t, J6.4 Hz, CH2), 7.16-7.36 (4H, m, 4aromatic-H). 0151 Preparation 12 (R32-pyridyl) 0152 N-(2-Pyridyl)-1,2-isothiazolidine-1,1-dioXide (4l) 0153 According to a similar method to that of Preparation 10, 3-chloropropylsulfonyl chloride was reacted with 2-aminopyridine to give N-(2-pyridyl)-3-chloropropylsulfonamide (intermediate 3l) as a pale yellow solid (yield 54%). To a solution of this intermediate 3l (2.138 g, 9.11 mmol) in DMF (30 ml) was added sodium hydride (60% in oil, 401 mg, 10 mmol) under ice-cooling. The resultant mixture was stirred for 30 minutes at 85 C. and the solvent was removed in vacuo. The residue was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of ethyl acetate/n-hexane (1:1), 1.806 g (100%) of the desired compound 4l was obtained as a yellow solid. IR (CHCl3)cm1: 3022, 1592, 1473, 1434, 1139. NMR (CDCl3) : 2.47-2.60 (2H, m, CH2), 3.43 (2H, t, J7.5 Hz, CH2), 4.05 (2H, t, J6.6 Hz, CH2), 6.88-7.02 (1H, m, CH), 7.26-7.35 (1H, m, CH), 7.58-7.70 (1H, m, CH), 8.33 (1H, d, J4.4 Hz, CH). 0154 Preparation 13 (R33-pyridyl) 0155 N-(3-Pyridyl)-1,2-isothizolidine-1,1-dioxide (4m) 0156 According to a similar method to that of Preparation 10, 3-chloropropylsulfonyl chloride 1 (7.28 g, 41.1 mmol) was reacted with 3-aminopyridine (4.6 g, 49.3 mmol) in pyridine (15 ml) to give 4.50 g (46%) of crude N-(3-pyridyl)-3-chloropropylsulfonamide (intermediate 3m) as a colorless solid. 0157 The intermediate 3m (232 mg, 0.988 mmol) was treated with sodium hydride (60% in oil, 43.5 mg, 1.09 mmol) in DMF (5 ml) in a similar manner as described in Preparation 12 to give 190 mg (97%) of the desired compound 4m as a colorless solid. IR (CHCl3)cm1: 3022, 2960, 1590, 1484, 1428, 1319, 1142. NMR (CDCl3) : 2.53-2.67 (2H, m, CH2), 3.38-3.45 (2H, m, CH2), 3.83 (2H, t, J6.6 Hz, CH2), 7.28-7.36 (1H, m, CH), 7.73-7.79 (1H, m, CH), 8.41 (1H, d, J4.6 Hz, CH), 8.46 (1H, d, J2.4 Hz, CH). 0158 Preparation 14 (R34-pyridyl) 0159 N-(4-Pyridyl)-1,2-isothiazolidine-1,1-dioxide (4n) 0160 To a solution of 3-chloropropylsulfonyl chloride 1 (3 ml, 24.7 mmol) and 4-aminopyridine (2.32 g, 24.7 mmol) in DMF (25 ml) was slowly added sodium hydride (60% in oil, 2.17 g, 54.3 mmol) over about 5 minutes with stirring under ice-cooling. The stirring was then continued for another 30 minutes at 50 C. The reaction mixture was concentrated in vacuo, the residue was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of methylene chloride/methanol (10:1), 1.294 (27%) of the desired compound 4n was obtained as a yellow solid. IR (ClCl3)cm1: 3024, 2956, 1597, 1504, 1320, 1143. NMR (CDCl3) : 2.53-2.67 (2H, m, CH2), 3.43 (2H, t, J7.6 Hz, CH2), 3.81 (2H, t, J6.6 Hz, CH2), 7.08 (2H, d, J5.4 Hz, CH), 8.49 (2H, d, J5.4 Hz, CH). 11

0161 Preparation 15 (R3Et) 0162 (E)-2-Ethyl-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Ia) 0163 To diisopropylamine (15.5 ml, 110.6 mmol) was dropwise added in an ice-water bath n-butyllithium in n-hexane (1.6 M, 69.5 ml, 111 mmol) over 20 minutes with stirring. After completion of the addition, stirring was conducted for another 15 minutes. The reaction mixture was cooled to 78 C. and added THF (100 ml). To the reaction mixture was dropwise added a solution of N-ethyl-1,2-isothiazolidine-1,1-dioxide 4a (15 g, 100.5 mmol), 3,5-di-tert-butyl-4-methoxymethoxybenzaldehyde 6a (25 g, 90.5 mmol) and HMPA (30 ml) in the THF (70 ml) over 15 minutes with stirring. The reaction mixture was stirred for another 30 minutes at the same temperature, warmed to room temperature, poured into cold 2N HCl (100 ml) and extracted with ethyl acetate (2250 ml). The ethyl acetate phase was washed with a dilute aqueous solution of sodium bicarbonate (300 ml) and a saturated brine (300 ml), dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was subjected to column chromatography on silica gel eluting with n-hexane/ethyl acetate (4:1 to 1:1) to give 21.3 g (55%) of aldol adduct 7a as a colorless solid. 0164 To a solution of the aldol adduct 7a (8.5 g, 19.9 mmol) in toluene (150 ml) was added p-toluenesulfonic acid hydrate (2.49 g, 13 mmol). The resultant mixture was heated to reflux for 30 minutes and then poured into a dilute aqueous solution of sodium bicarbonate (150 ml) and extracted with ethyl acetate (150 ml2). The organic layer was washed with water (150 ml) and a saturated brine (150 ml), dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was subjected to column chromatography on silica gel. From the fraction eluted with n-hexane/ethyl acetate (3:1), the desired compound Ia (2.59 g, 36%) was yielded. M.p.135-137 C. IR (KBr)cm1: 3610, 3440, 2970, 2880, 1645, 1597, 1430, 1290, 1173, 1151, 1139. NMR (CDCl3) : 1.29 (3H, t, J7.2 Hz, CH3), 1.45 (18H, s, 2But), 3.07-3.19 (4H, m, CH2), 3.28 (2H, q, J7.2 Hz, CH2), 5.50 (1H, s, OH), 7.24-7.26 (3H, m, 2aromatic-H, CH). Elementary analysis (C20H31NO3S) Calcd: C, 65.71; H, 8.55; N, 3.83; S, 8.77. Found: C, 65.65; H, 8.43; N, 3.85; S, 8.78. 0165 Preparation 16 (R3CH3) 0166 (E)-2-Methyl-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Ib) 0167 According to a similar method to that of Preparation 15, an aldol reaction was carried out using compound 6a (3.34 g, 12 mmol) and N-methyl-1,2-isothiazolidine-1,1-dioxide 4b (1.35 g, 10 mmol) to give 1.65 g (40%) of adduct 7b. To a solution of the adduct 7b (1.60 g, 3.87 mmol) in toluene (30 ml) was added p-toluenesulfonic acid hydrate (160 mg) and the resultant mixture was heated to reflux for 30 minutes. The reaction product was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of n-hexane/ethyl acetate (3:7), the desired compound Ib (580 mg, 43%) was obtained. 0168 M.p.168-170 C. IR (CHCl3)cm1: 3620, 2956, 1435, 1292, 1218, 1149. NMR (CDCl3) : 1.45 (18H, s, 2But), 2.76 (3H, s, NCH3), 3.07-3.18 (2H, m, CH2), 3.20-3.32 (2H, m, CH2), 5.51 (1H, s, OH), 7.23-7.29 (3H, m, 2aromatic-H, CH). Elementary analysis (C19H29NO3S) Calcd: C, 64.92; H, 8.32; N, 3.98; S, 9.12. Found: C, 64.62; H, 8.31; N, 3.95; S, 9.14. 0169 Preparation 17 (R3CH2CH(CH3)2) 0170 (E)-2-Isobutyl-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Ic) 0171 According to a similar method to that of Preparation 15, an aldol reaction was carried out using compound 6a (2.78 g, 10 mmol) and N-isobutyl-1,2-isothiazolidine-1,1-dioxide 4c (1.95 g, 11 mmol) to give 3.67 g (81%) of adduct 7c. 0172 This adduct 7c (3.60 g, 7.9 mmol) was treated in toluene (50 ml) with p-toluenesulfonic acid hydrate (360 mg) in a similar manner as that of Preparation 15. The product was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of n-hexane-ethyl acetate (1:3), the desired compound Ic (1.30 g, 42%) was obtained. M.p.167-170 C. IR (CHCl3)cm1: 3620, 2956, 1646, 1435, 1289, 1240, 1148, 1081. NMR (CDCl3) : 0.97 (6H, d, J6.4 Hz, (CH3)2), 1.45 (18H, s, 2But), 1.81-2.02 (1H, m, CH), 2.87 (2H, d, J7.4 Hz, CH2), 3.06-3.18 (2H, m CH2), 3.22-3.33 (2H, m, CH2), 5.50 (1H, s, OH), 7.23-7.27 (3H, m, 2aromatic-H, CH). 0173 Elementary analysis (C22H35NO3S) Calcd: C, 67.14; H, 8.96; N, 3.56; S, 8.15. Found: C, 66.85; H, 8.99; N, 3.58; S, 8.11. 0174 Preparation 18 (R3Cyclopropyl) 0175 (E)-2-Cyclopropyl-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Id) 0176 According to a similar method to that of Preparation 15, an aldol reaction was carried out using compound 6a (2.67 g, 9.6 mmol) and N-cyclopropyl-1,2-isothiazolidine-1,1-dioxide 4d (1.29 g, 8.0 mmol) to give 3.09 g (88%) of adduct 7d. The adduct 7d (3.0 g, 7 mmol) was treated in toluene (50 ml) together with p-toluenesulfonic acid hydrate (300 mg). The reaction product was purified in a similar manner as that of Preparation 17 to give 1.03 g (40%) of the desired compound Id. M.p.202-204 C. IR (CHCl3)cm1: 3620, 2956, 1434, 1297, 1237, 1145. NMR (CDCl3) : 0.68-0.90 (4H, m, 2CH2), 1.44 (18H, s, 2But), 2.28-2.40 (1H, m, CH), 3.08 (2H, dt, J2.6, 6.7 Hz, CH2), 3.36 (2H, t, J6.7 Hz, CH2), 5.51 (1H, s, OH), 7.20-7.25 (3H, m, 2aromatic-H, CH). Elementary analysis (C21H31NO3S) Calcd: C, 66.81; H, 8.28; N, 3.71; S, 8.49. Found: C, 66.67; H, 8.29; N, 3.71; S, 8.38. 0177 Preparation 19 (R3CH2CH2CH3) 0178 (E)-2-n-Propyl-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Ie) 0179 According to a similar method to that of Preparation 15, an aldol reaction was carried out using compound 6a (2.78 g, 10 mmol) and N-n-propyl-1,2-isothiazolidine-1,1-dioxide 4e (1.35 g, 8.27 mmol) to give 1.5 g (41%) of adduct 7e. The adduct 7e was treated with p-toluenesulfonic acid hydrate (400 mg) in a manner as described in Preparation 15. The reaction product was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of n-hexane-ethyl acetate (1:4), the desired compound Ie (810 mg, 26%) was obtained. M.p.181-183 C. IR (CHCl3)cm1: 3616, 2954, 1435, 1289, 1146. NMR (CDCl3)cm1: 0.98 (3H, t, J7.4 Hz, CH3), 1.45 (18H, s, 2But), 1.57-1.78 (2H, m, CH2), 2.98-3.20 (4H, m, 2CH2), 3.22-3.34 (2H, m, CH2), 5.50 (1H, s, OH), 7.23-7.27 (3H, m, 2aromatic-H, CH). Elementary analysis (C21H33NO3S) Calcd: C, 66.45; H, 8.76; N, 3.69; S, 8.45. Found: C, 66.25; H, 8.74; N, 3.70; S, 8.33. 0180 Preparation 20 (R3OCH3) 0181 (E)-2-Methoxy-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidin e-1,1-dioxide (If) and its (Z)-isomer (9f) 0182 According to a similar method to that of Preparation 15, an aldol reaction was carried out using compound 6a (5.56 g, 20 mmol) and N-methoxy-1,2-isothiazolidine-1,1-dioxide 4f (3.32 g, 22 mmol) to give 6.89 g (80%) of adduct 7f. The adduct 7f (6.89 g, 16 mmol) was treated in toluene (100 ml) with p-toluenesulfonic acid hydrate (1 g) in a manner as described in Preparation 15. The reaction product was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of n-hexane-ethyl acetate (6:1), the desired compound If (2.40 g, 41%) was obtained. M.p.166-168 C. IR (CHCl3)cm1: 3616, 2952, 1639, 1436, 1340, 1240, 1158, 1002. NMR (CDCl3) : 1.45 (18H, s, 2But), 3.11 (2H, dt, J2.2, 7.0 Hz, CH2), 3.66 (2H, t, J7 Hz, CH2), 3.81 (3H, s, OCH3), 5.55 (1H, s, OH), 7.25-7.35 (3H, m, 3aromatic-H, CH). Elementary analysis (C19H29NO4S) Calcd: C, 62.10; H, 7.95; N, 3.81; S, 8.72. Found: C, 61.90; H, 7.88; N, 3.91; S, 8.67. 0183 Preparation 21 (R3OCH2C6H5) 0184 (E)-2-Benzyloxy-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Ig) 0185 According to a similar method to that of Preparation 15, an aldol reaction was carried out using compound 6a (15 g, 54 mmol) and N-benzyloxy-1,2-isothiazolidine-1,1-dioxide 4g (10.23 g, 45 mmol) to give 15.51 g (68%) of adduct 7g. The adduct 7g (10.21 g, 20.2 mmol) was treated in toluene (150 ml) with p-toluenesulfonic acid hydrate (1 g) in a manner as described in Preparation 15. The reaction product was filtered through a small amount of silica gel, and the filtrate was concentrated in vacuo to give 5.32 g (59%) of the desired compound Ig. M.p.134-135 C. IR (CHCl3)cm1: 3620, 2956, 1639, 1436, 1339, 1241, 1159. NMR (CDCl3) : 1.44 (18H, s, 2But), 3.09 (2H, dt, J2.6, 6.8 Hz, CH2), 3.58 (2H, t, J6.8 Hz, CH2), 5.02 (2H, s, OCH2), 5.53 (1H, s, OH), 7.25-7.45 (8H, m, 7aromatic-H, CH). Elementary analysis (C25H33NO4S) Calcd: C, 67.69; H, 7.50; N, 3.16; S, 7.23. Found: C, 67.52; H, 7.59; N, 3.18; S, 7.16. 0186 Preparation 22 (R34-methoxybenzyl) 0187 (E)-2-(4-Methoxybenzyl)-5-(3,5-di-tert-butyl)benzylidene-1,2-isothiazolidine-1,1-dioxide (Ih) 0188 According to a similar method to that of Preparation 15, an aldol reaction was carried out using compound 6a (9 g, 32 mmol) and N-(4-methoxybenzyl)-1,2-isothiazolidine-1,1-dioxide 4h (7.24 g, 30 mmol) to give 13.61 g (84%) of adduct 7h. The adduct 7h (12.6 g, 24.2 mmol) was treated in toluene (150 ml) with p-toluenesulfonic acid hydrate (1.3 g) in a manner as described in Preparation 15 to give 8.83 g of the desired compound Ih. 0189 Preparation 23 (R33,4-dimethoxybenzyl) 0190 (E)-2-(3,4-Dimethoxybenzyl)-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Ii) 0191 According to a similar method to that of Preparation 15, an aldol reaction was carried out using compound 6a (5.6 g, 20 mmol) and N-(3,4-dimethoxy)benzyl-1,2-isothiazolidine-1,1-dioxide 4i (5.85 g, 21.6 mmol) to give 9.25 g (78%) of adduct 7i. From the adduct 7i (4 g, 7.3 mmol), the desired compound Ii (2.5 g) was obtained by dehydration and deprotection in a manner as described in Preparation 15. 0192 Preparation 24 (R 3C6H5) 0193 (E)-2-Phenyl-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Ij) 0194 According to a similar method to that of Preparation 15, an aldol reaction was carried out using compound 6a (2.47 g, 8.88 mmol) and N-phenyl-1,2-isothiazolidine-1,1-dioxide 4j (2.19 g, 11.10 mmol) to give 3.184 g (75%) of adduct 7j. The adduct 7j (3.184 g, 6.69 mmol) was treated in toluene (100 ml) with p-toluenesulfonic acid hydrate (750 mg) to give the desired compound Ij (667 mg, 24%). M.p.195-196 C. IR (KBr)cm1: 3560, 3520, 2960, 1636, 1593, 1492, 1430, 1295, 1268, 1105, 1092. NMR (CDCl3) : 1.47 (18H, s, 2But), 3.31 (2H, dt, J2.6, 6.6 Hz, CH2), 3.80 (2H, t, J6.6 Hz, CH2), 5.54 (1H, s, OH), 7.17-7.26 (2H, m, aromatic-H, CH), 7.29 (2H, s, 2aromatic-H), 7.38-7.42 (4H, m, 4aromatic-H). Elementary analysis (C24H31NO3S0.1H2O) Calcd: C, 69.39; H, 7.61; N, 3.37; S, 7.72. Found: C, 69.27; H, 7.60; N, 3.39; S, 7.61. 0195 Preparation 25 (R34-chlorophenyl) 0196 (E)-2-(4-Chlorophenyl)-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Ik) 0197 According to a similar method to that of Preparation 15, an aldol reaction was carried out using compound 6a (2.25 g, 8.09 mmol) and N-(4-chlorophenyl)-1,2-isothiazolidine-1,1-dioxide 4k (2.34 g, 10.1 mmol) to give 2.54 g (62%) of adduct 7k. The adduct 7k (2.53 g, 4.96 mmol) was treated in toluene (70 ml) with p-toluenesulfonic acid hydrate (250 mg) to give the desired compound Ik (859 mg, 39%). M.p.245-246 C. IR (KBr)cm1: 3560, 2960, 1644, 1592, 1491, 1430, 1280, 1105, 1090. NMR (CDCl3) : 1.46 (18H, s, 2But), 3.30 (2H, dt, J2.6, 6.6 Hz, CH2), 3.76 (2H, t, J6.6 Hz, CH2), 5.55 (1H, s, OH), 7.28 (2H, s, 2aromatic-H), 7.26-7.40 (5H, m, 4aromatic-H, CH). Elementary analysis (C24H30NO3SCl) Calcd: C, 64.34; H, 6.75; N, 3.13; S, 7.16; Cl, 7.91. Found: C, 64.59; H, 6.78; N, 3.28; S, 7.17; Cl, 7.87. 0198 Preparation 26 (R32-pyridyl) 0199 (E)-2-(2-Pyridyl)-5-(3,5-di-tert-butyl-4-hydroxy benzylidene-1,2-isothiazolidine-1,1-dioxide (Il) 0200 According to a similar method to that of Preparation 15, an aldol reaction was carried out using compound 6a (208 mg, 0.75 mmol) and N-(2-pyridyl)-1,2-isothiazolidine-1,1-dioxide 4l (149 mg, 0.75 mmol) to give 233 mg (65%) of adduct 7l. The adduct 7l (231 mg, 0.485 mmol) was treated in toluene (5 ml) with p-toluenesulfonic acid hydrate (60 mg) to give the desired compound Il (96 mg, 48%). M.p.177-179 C. IR (KBr)cm1: 3570, 2960, 1646, 1600, 1587, 1472, 1431, 1300, 1105, 1085. NMR (CDCl3) : 1.47 (18H, s, 2But), 3.31 (2H, dt, J2.4, 6.8 Hz, CH2), 4.08 (2H, t, J6.8 Hz, CH2), 5.55 (1H, s, OH), 6.99-7.05 (1H, m, CH), 7.28 (2H, s, 2aromatic-H), 7.38 (1H, t, J2.4 Hz, Py-H), 7.55-7.74 (2H, m, 2Py-H), 8.33-8.36 (1H, m, Py-H). Elementary analysis (C23H30N2O3S) Calcd: C, 66.63; H, 7.29; N, 6.76; S, 7.73. Found: C, 66.31; H, 7.30; N, 6.72; S, 7.66. 0201 Preparation 27 (R33-pyridyl) 0202 (E)-2-(3-Pyridyl)-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Im) 0203 According to a similar method to that of Preparation 15, an aldol reaction was carried out using compound 6a (1.474 g, 5.30 mmol) and N-(3-pyridyl)-1,2-isothiazolidine-1,1-dioxide 4m (1.051 g, 5.30 mmol) to give 1.522 g (60%) of adduct 7m. The adduct 7m (1.522 g, 3.19 mmol) was treated in toluene (40 ml) with p-toluenesulfonic acid hydrate (400 mg) to give 358 mg (27%) of the desired compound Im. M.p.207-209 C. IR (KBr)cm1: 3625, 3040, 2960, 1640, 1590, 1480, 1431, 1305, 1152. NMR (CDCl3) : 1.47 (18H, s, 2But), 3.36 (2H, dt, J2.4, 6.4 Hz, CH2), 3.84 (2H, t, J6.4 Hz, CH2), 5.59 (1H, s, OH), 7.29 (2H, s, 2aromatic-H), 7.29-7.40 (2H, m, CH, Py-H), 7.84-7.93 (1H, m, Py-H), 8.37-8.64 (2H, m, 2Py-H). Elementary analysis (C23H30N2O3S) Calcd: C, 66.63; H, 7.29; N, 6.76; S, 7.73. Found: C, 66.31; H, 7.27; N, 6.69; S, 7.47. 0204 Preparation 28 (R34-pyridyl) 0205 (E)-2-(4-Pyridyl)-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (In) 0206 According to a similar method to that of Preparation 15, an aldol reaction was carried out using compound 6a (2.59 g, 9.36 mmol) and N-(4-pyridyl)-1,2-isothiazolidine-1,1-dioxide 4n (2.05 g, 10.4 mmol) to give 2.721 g (61%) of adduct 7n. The adduct 7n (1.65 g, 3.46 mmol) was treated in toluene (80 ml) with p-toluenesulfonic acid hydrate (433 mg) to give 658 mg (46%) of the desired compound In. M.p.213-214.5 C. IR (kBr)cm1: 3400, 2955, 1643, 1591, 1502, 1437, 1316, 1153. NMR (CDCl3) : 1.47 (18H, s, 2But), 3.37 (2H, dt, J2.2, 6.8 Hz, CH2), 3.82 (2H, t, J6.8 Hz, CH2), 5.61 (1H, s, OH), 7.21-7.25 (4H, m, 2aromatic-H, 2Py-H), 7.42 (1H, t, J2.2 Hz, CH), 8.50-8.58 (2H, m, 2Py-H). Elementary analysis (C23H30N2O3S) Calcd: C, 66.63; H, 7.29; N, 6.76; S, 7.73. Found: C, 66.46; H, 7.18; N; 6.66; S, 7.49. 12

0207 Preparation 29 (R3H) (YCO2C(CH3)3) 0208 (E)-5-(3,5-Di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (10) 0209 According to a similar method to that of Preparation 15, an aldol reaction was carried out using compound 6a and N-(tert-butoxycarbonyl)-1,2-isothiazolidine-1,1-dioxide 4o, which had been prepared from starting materials, 3-chloropropylsulfonyl chloride and tert-butyl carbonate, in accordance with the method of reaction scheme I, to give a crude adduct 7o. To a solution of the crude adduct 7o in toluene was added p-toluenesulfonic acid hydrate and the resultant mixture was heated to reflux for 45 minutes and then subjected to column chromatography on silica gel. From the fraction eluted with a mixture of n-hexane/ethyl acetate (2:1), the desired compound 10 (yield 8.5%) was obtained. M.p.233-234 C. IR (CHCl3)cm1: 3618, 2952, 1435, 1366, 1311, 1240, 1155, 1070. NMR (CDCl3) : 1.45 (18H, s, 2But), 3.18 (2H, dt, J2.6, 6.8 Hz, CH2), 3.42-3.60 (2H, m, CH2), 4.05-4.25 (1H, broad, NH), 5.52 (1H, s, OH), 7.22-7.27 (3H, m, 2aromatic-H, CH). Elementary analysis (C18H27NO3S0.35H2O) Calcd: C, 62.89; H, 8.12; N, 4.07; S, 9.38. Found: C, 63.10; H, 7.90; N, 4.17; S, 9.11. 0210 Preparation 30 (R3H) (Y4-methoxybenzyl) 0211 (Z)-5-(3,5-Di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (10) 0212 To a solution of the adduct 7h (13.16 g, 25.3 mmol) of the aldol reaction, which was obtained in a manner as described in Preparation 22, in toluene (150 ml) was added p-toluenesulfonic acid hydrate (1.3 g). The resultant mixture was heated to reflux for 30 minutes and filtered through a small amount of silica gel. The solvent was removed in vacuo to give a mixture (8.83 g) of crude (E)- and (Z)-2-(4-methoxybenzyl)-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxides. To a solution of the mixture in methylene chloride (150 ml) was added titanium tetrachloride (4.1 ml). The resultant mixture was stirred for 30 minutes at 0 C. and then subjected to column chromatography on silica gel. From the fraction eluted with a mixture of n-hexane/ethyl acetate (1:1), compounds 10 (3.35 g, 41%) was obtained. Compound 10 was identical with the sample obtained in Preparation 29. 0213 Preparation 31 (R3H)(Y3,4-dimethoxybenzyl) 0214 To a solution of the adduct 7i (4.0 g, 7.3 mmol) of the aldol reaction obtained in Preparation 9 in xylene (50 ml) were added an equimolar amount of each of 2,6-di-tert-butylphenol, anisole and p-toluenesulfonic acid hydrate. The resultant mixture was heated to reflux for 45 minutes, and the reaction product was subjected to column chromatography on silica gel to give compounds 10 (580 mg, 24%). Compound 10 was identical with the samples obtained in Preparations 29 and 30, respectively. 13

0215 Preparation 32 (R3CH2CO2C2H5) 0216 (E)-2-Ethoxycarbonylmethyl-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Ip) 0217 (E)-5-(3,5-Di-tert-butyl-4-hydroxy)benzylidenel, 2-isothiazolidine-1,1-dioxide 10 (500 mg, 1.48 mmol), ethyl iodoacetate (240 l, 2 mmol), an aqueous solution of 2N sodium hydroxide (1.5 ml, 3 mmol) and a small amount of N-benzyltrimethylammonium chloride were sequentially added to a mixture of chloroform (20 ml) and water (10 ml). The resultant mixture was stirred for 24 hours at room temperature and then treated in a conventional manner. The product was purified by column chromatography on silica gel to give 300 mg (49%) of the desired compound Ip. IR (CHCl3)cm1: 3620, 2956, 1747, 1435, 1298, 1229, 1160. NMR (CDCl3) : 1.29 (3H, t, J7.2 Hz, CH3), 1.45 (18H, s, 2But), 3.19 (2H, dt, J2.6, 6.6 Hz, CH2), 3.51 (2H, t, J6.6 Hz, CH2), 3.87 (2H, s, CH2CO), 4.23 (2H, q, J7.2 Hz, CH2), 5.52 (1H, s, OH), 7.22-7.30 (3H, m, 2aromatic-H, CH). 0218 Preparation 33 (R3CH2COOH) 0219 (E)-2-Carboxymethyl-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Iq) 0220 Compound Ip (610 mg, 1.44 mmol) as obtained in a similar manner as described in Preparation 32 and an aqueous solution of 2N sodium hydroxide (1.5 ml) were added to a mixture of THF (10 ml) and methanol (4 ml). The resultant mixture was stirred at 0 C. for 30 minutes. After the addition of ethyl acetate (50 ml), the reaction mixture was washed with an aqueous solution of 1N hydrochloric acid (20 ml), then a saturated brine (20 ml), and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give 445 mg (78%) of the desired compound Iq. M.p175-178 C. IR (CHCl3)cm1: 3620, 2954, 1735, 1435, 1297, 1240, 1149. NMR (CDCl3) : 1.45 (18H, s, 2But), 3.20 (2H, dt, J2.6, 6.6 Hz, CH2), 3.51 (2H, t, J6.6 Hz, CH2), 3.95 (2H, s, CH2CO), 5.54 (1H, s, OH), 7.25 (2H, s, 2aromatic-H). Elementary analysis (C20H29NO5S) Calcd: C, 60.46; H, 7.41; N, 3.53; S, 8.07. Found: C, 60.34; H, 7.40; N, 3.56; S, 8.04. 0221 Preparation 34 (R3CH2CH2OH) 0222 (E)-2-(2-Hydroxyethyl)-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1.1-dioxide (Ir) 0223 Compound 10 (675 mg, 2 mmol), 2-iodoethanol (624 l, 8 mmol), an aqueous solution of 2N sodium hydroxide (2 ml) and a small amount of N-benzyltrimethylammonium chloride were added to a mixture of methylene chloride (20 ml) and water (10 ml). The resultant mixture was heated to reflux for 3 days and treated in a conventional manner and the product was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of n-hexane/ethyl acetate (7:3), 190 mg (25%) of the desired compound Ir was obtained. M.p.156-157 C. IR (CHCl3)cm1: 3620, 2950, 1434, 1290, 1240, 1151, 1066. NMR (CDCl3) : 1.45 (18H, s, 2But), 3.16 (2H, dt, J2.4, 6.5 Hz, CH2), 3.30 (2H, m, CH2), 3.41 (2H, t, J6.5 Hz, CH2), 3.87 (2H, t, J5.2 Hz), 5.53 (1H, s, OH), 7.23-7.29 (3H, m, 2aromatic-H, CH). Elementary analysis (C20H31NO4S) Calcd: C, 62.96; H, 8.19; N, 3.67; S, 8.40. Found: C, 62.72; H, 8.27; N, 3.69; S, 8.21. 0224 Preparation 35 (R3CH2CH2N(CH3)2) 0225 (E)-2-(2-Dimethylamino) ethyl)-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Is) 0226 Compound 10 (843 mg, 2.5 mmol), N,N-dimethyl-2-bromoethylamine (750 mg, 5 mmol), an aqueous solution of 2N sodium hydroxide (3 ml, 6 mmol) and a small amount of N-benzyltrimethylammonium chloride were added to a mixture of chloroform (30 ml) and water (10 ml). The resultant mixture was stirred for 2 hours under ice-cooling. The chloroform layer was washed with water (20 ml2) and dried over anhydrous sodium sulfate. Chloroform was removed in vacuo to give 950 mg (93%) of the desired compound as a crystalline residue. M.p.160-165 C. IR (CHCl3)cm1: 3620, 2956, 1435, 1290, 1148. NMR (CDCl3) : 1.45 (18H, s, 2But), 2.29 (6H, s, N(CH3)2), 2.60 (2H, t, J6.6 Hz, CH2), 3.12 (2H, dt, J2.2, 6.6 Hz, CH2), 3.20 (2H, t, J6.6 Hz, CH2), 3.38 (2H, t, J6.6 Hz, CH2), 5.51 (1H, s, OH), 7.21-7.28 (3H, m, 2aromatic-H, CH). Elementary analysis (C22H36N2O3S0.2CH2Cl2) Calcd: C, 62.65; H, 8.62; N, 6.58; S, 7.53; Cl, 3.33. Found: C, 62.32; H, 8.60; N, 6.71; S, 7.56; Cl, 3.24. 0227 Preparation 36 (R3COCH3) 0228 (E)-2-Acetyl-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (It) 0229 To a solution of compound 10 (585 mg, 1.74 mmol) in pyridine (10 ml), a small amount of 4-N,N-dimethylaminopyridine was added, and acetic anhydride (6 ml) was dropwise added under ice-cooling. The resultant mixture was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and the solution was filtered through a small amount of silica gel. The solvent was removed in vacuo to give 360 mg (55%) of the desired compound as a crystal-like residue. M.p.177-179 C. IR (CHCl3)cm1: 3618, 2958, 1695, 1435, 1379, 1297, 1153, 1117. NMR (CDCl3) : 1.46 (18H, s, 2But), 2.53 (3H, s, COCH3), 3.20 (2H, dt, J2.2, 7.0 Hz, CH2), 3.86 (2H, t, J7.0 Hz, CH2), 5.60 (1H, s, OH), 7.52 (2H, s, 2aromatic-H), 7.39 (1H, t, J2.2 Hz, CH). Elementary analysis (C20H29NO4S) Calcd: C, 63.30; H, 7.70; N, 3.69; S, 8.45. Found: C, 63.27; H, 7.83; N, 3.64; S, 8.22. 0230 Preparation 37 ((R3N-methyl-N-methoxy)carbamoyl) 0231 (E)-2-(N-Methyl-N-methoxy)carbamoyl-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Iu) 0232 Compound 10 (450 mg, 1.33 mmol) and N-methyl-N-methoxy-O-phenyl carbamate (300 mg, 1.66 mmol) were dissolved in a mixture of THF (10 ml) and HMPA (10 ml). To the solution was dropwise added absolution of lithium hexamethyldisilazane (LiHMDS) in THF (1 M, 3.2 ml) with stirring and cooling to 40 C. The reaction mixture was warmed to room temperature and poured into an aqueous solution of 1N hydrochloric acid (20 ml). The mixture was extracted with ethyl acetate (30 ml), and then the ethyl acetate layer was washed with water (30 ml) and a saturated brine (30 ml), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of n-hexane/ethyl acetate (7:3), the desired compound Iu (230 mg, 41%) was obtained. IR (CHCl3)cm1: 3620, 2958, 1673, 1435, 1388, 1330, 1240, 1207, 1155, 1092. NMR (CDCl3) : 1.45 (18H, s, 2But), 3.21 (2H, dt, J2.2, 6.8 Hz, CH2), 3.31 (3H, s, NCH3), 3.78 (3H, s, OCH3), 3.89 (2H, t, J6.8 Hz), 5.54 (1H, s, OH), 7.23 (2H, s, 2aromatic-H), 7.31 (1H, t, J2.2 Hz, CH). 0233 Preparation 38 ((R3N-benzyloxy-N-methoxymethyl)carbamoyl) 0234 (E)-2-(N-Benzyloxyl-N-methoxymethyl)carbamoyl-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Iv) 0235 Compound 10 (424 mg, 1.26 mmol) and N-benzyloxy-N-methoxymethyl-O-phenyl carbamate (722 mg, 2.52 mmol) were treated in a mixture of THF (90 ml) and HMPA (30 ml) with a solution of LIHMDS in THF (1 M, 4.0 ml), in a manner as described in Preparation 37. The reaction product was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of n-hexane/ethyl acetate (3:1), the desired compound Iv (600 mg, 90%) was obtained. NMR (CDCl3) : 1.45 (18H, s, 2But), 3.18 (2H, dt, J2.0, 6.8 Hz, CH2), 3.45 (3H, s, OCH3), 3.79 (2H, t, J6.8 Hz, CH2), 4.94 (2H, s, OCH2), 5.02 (2H, s, OCH2), 5.54 (1H, s, OH), 7.22 (2H, s, 2aromatic-H), 7.30 (1H, t, J2.0 Hz, CH), 7.30-7.55 (5H, m, 5aromatic-H). 0236 Preparation 39 (R3CONHOH) 0237 (E)-2-(Hydroxycarbamoyl)-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1.2-isothiazolidine-1,1-dioxide (Iw) 0238 To a solution of compound Iv (600 mg, 1.13 mmol) obtained in Preparation 38 in methylene chloride (8 ml) was added titanium tetrachloride (500 l, 4.56 mmol) under ice-cooling, and the resultant mixture was stirred for 1.5 hours. After an aqueous solution of 2N hydrochloric acid (10 ml) was added, the reaction mixture was stirred for 30 minutes at room temperature and then extracted with methylene chloride (20 ml). The organic layer was washed with a saturated brine (20 ml), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of n-hexane/ethyl acetate (1:1), the desired compound Iw (150 mg, 33%) was obtained. IR (CHCl3)cm1: 3618, 2956, 1707, 1434, 1320, 1151, 1100. NMR (CDCl3) : 1.45 (18H, s, 2But), 3.23 (2H, dt, J2.2, 7.0 Hz, CH2), 3.94 (2H, t, J7.0 Hz, CH2), 5.61 (1H, s, OH), 6.85-6.95 (1H, broad, OH), 7.24 (2H, s, 2aromatic-H), 7.30 (1H, t, J2.2 Hz, CH), 8.61 (1H, s, NH). 14

0239 Preparation 40 0240 (E)-2-Hydroxy-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (12) 0241 According to a similar method to that of Preparation 15, an aldol reaction was carried out using compound 6a and N-benzyloxy-1,2-isothiazolidine-1,1-dioxide. The adduct obtained by the aldol reaction was then treated with p-toluenesulfonic acid hydrate to give crude 2-benzyloxy-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide 11. To a solution of the crude dioxide (4.44 g, 10 mmol) in methylene chloride (80 ml) was dropwise added titanium tetrachloride (4.4 ml, 40 mmol) with stirring and ice-cooling, and the mixture was stirred for another 2 hours at the same temperature. An aqueous solution of 1N hydrochloric acid (50 ml) was added to the reaction mixture. The methylene chloride layer was separated, washed sequentially with water (50 ml) and a saturated brine (50 ml), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of n-hexane/ethyl acetate (3:1), the desired compound 12 (1.6 g, 45%) was obtained. M.p.177-182 C. (decomp.). IR (KBr)cm1: 3560, 3430, 1425, 1330, 1240, 1155, 1130, 1115. NMR (CDCl3) : 1.45 (18H, s, 2But), 3.18 (2H, dt, J2.6, 6.8 Hz, CH2), 3.89 (2H, t, J6.8 Hz, CH2), 5.56 (1H, s, OH), 6.18-6.30 (1H, broad, OH), 7.26-7.35 (3H, m, 2aromatic-H, CH). Elementary analysis (C18H27NO4S) Calcd: C, 61.16; H, 7.70; N, 3.96; S, 9.07. Found: C, 60.86; H, 7.68; N, 3.93; S, 8.90. 0242 Preparation 41 0243 (E)-2-Isopropyl-5-(3,5-di-tert-butyl-4-hydroxy)benzylidene-1,2-isothiazolidine-1,1-dioxide (Ix) 15

0244 According to a similar method to that of Preparation 15, an aldol reaction was carried out using N-isopropyl-1,2-isothiazolidine-1,1-dioxide 4p (3.65 g, 22.4 mmol) and 3,5-di-tert-butyl-4-methoxymethoxybenzaldehyde 6a (5.28 g, 19.0 mmol) to give 6.27 g (74.7%) of adduct 7p as a white powder. To a solution of the adduct 7p (6.27 g) in toluene (120 ml) was added p-toluenesulfonic acid hydrate (600 mg). The mixture was heated to reflux for 30 minutes, cooled, washed twice with water (100 ml), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crystalline residue was recrystallized from methanol to give 2.16 g (30%) of the desired compound Ix as colorless columnar crystals. M.p.148-150 C. IR (KBr)cm1: 3550, 2960, 1645, 1600, 1432, 1273, 1173. NMR (CDCl3) : 1.29 (6H, d, J6.6 Hz, 2CH3), 1.45 (18H, s, 2But), 3.07-3.14 (2H, m, CH2), 3.29-3.35 (2H, m, CH2), 3.94 (1H, sept, CH), 5.48 (1H, s, OH), 7.22 (1H, t, J2.8 Hz, CH), 7.23 (2H, s, ArH). Elementary analysis (C21H33NO3S) Calcd: C, 66.45; H, 8.76; N, 3.69; S, 8.45. Found: C, 66.37; H, 9.01; N, 3.67; S, 8.28. 16

0245 Preparation 42 (R3CH2CH2CH3) 0246 N-n-Propyl-1,2-isothiazolidine-1,1-dioxide (4e) 0247 To -sultone (12.2 g, 0.1 mol) was added n-propylamine (5.9 g, 0.1 mmol) with stirring and ice-cooling. As the reaction proceeds, the contents solidified. To the solid product was added phosphorus oxychloride (10 ml). The reaction mixture was heated to reflux for 2 hours, and the remaining phosphorus oxychloride was removed under reduced pressure. After the addition of ether (100 ml) to the residue, insoluble substances were removed by filtration. The ether layer was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to give the desired compound 4e (15.2 g, 93%) as a colorless oil. This product was identical with the sample obtained in Preparation 5. 0248 Preparation 43 (R3CH2CH(CH3)2) 0249 N-Isobutyl-1,2-isothiazolidine-1,1-dioxide (4c) 0250 According to a similar method to that of Preparation 1, -sultone (12.2 g, 0.1 mol), isobutylamine (7.3 g, 0.1 mol) and phosphorus oxychloride (10 ml) were reacted to give the desired compound 4c (15.9 g, 90%). This product was identical with the sample obtained in Preparation 3. 0251 Novel compounds of the present invention can be prepared according to the following Examples, and the processes for the production described therein per se are not to be construed as limiting the present invention. One example of the processes for the production of the novel compounds of the present invention is provided below.

EXAMPLES

Example 10252

0253 a. 3,5-Diallyl-4-hydroxybenzaldehyde (23) 0254 The titled compound was synthesized according to the process described in the literature with a partial modification. See Claisen; Eisleb, Justus Liebigs Ann. Chem., 401, 108 (1913). 0255 b. 2,6-Diallyl-4-((2-ethyl-1,1-dioxo-1,2-isothiazolidin-5-yl)hydroxy-methyl)phenol (24) 0256 LDA (2.0 M solution in THF) (4.52 ml, 9.04 mmol) was dropwise and slowly added to a solution of 23 (850 mg, 4.20 mmol) and 2-ethyl-1,2-isothiazolidin-1,1-dioxide (752 mg, 5.04 mmol) in THF (15 ml), while maintaining the temperature below 45 C. The reaction mixture was warmed to 0 C. and stirred for another 1 hour. The mixture was added with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel to yield 1.083 g (73%) of 24 as a mixture of diastereomers: 1H NMR (CDCl3) : 1.23-1.28 (3H, m), 1.75-2.06 (2H*, m), 2.47-2.61 (2H*, m), 2.95-3.53 (9H, m), 4.79-5.42 (6H, m), 5.90-6.08 (2H, m), 7.02 (2H, s). 0257 c. 5-((tert-Butyl-dimethylsilanyloxy)-(3,3-diallyl-4-methoxymethoxyphenyl)-methyl)-2-ethyl-1,2-isothazolidin 1,1-dioxide (25) 0258 To a solution of 24 (1.789 g, 5.09 mmol) in dichloromethane (25 ml), under ice-cooling, diisopropylethylamine (4.43 ml, 25.45 mmol) and MOMCl (1.16 ml, 15.27 mmol) were dropwise added sequentially and slowly. After stirring at 0 C. for 1 hour and then at room temperature for 1 hour, the reaction mixture was added with diluted hydrochloric acid and extracted with chloroform. The organic layer was washed with water, saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel to yield 1.470 g (73%) of an intermediate. This intermediate (805 mg, 2.035 mmol) was dissolved in dichloromethane (10 ml), 2,6-lutidine (0.71 ml, 6.105 mmol) and TBSOTf (0.70 ml, 3.05 mmol) were added to the solution under ice-cooling, and the mixture was stirred for 2 hours. The mixture was added with diluted hydrochloric acid and extracted with chloroform. The organic layer was washed with water, saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel to yield 960 mg (92%) of 25. 1H NMR (CDCl3) : 0.25 (3H*, s), 0.23 (3H*, s), 0.08 (3H*, s), 0.11 (3H*, s), 0.83 (9H*, s), 0.86 (9H*, s), 1.20 (3H, t, J7.2 Hz), 1.60-2.54 (2H, m), 2.91-3.52 (9H, m), 3.58 (3H*, s), 3.59 (3H*, s), 4.80-5.12 (7H, m), 5.85-6.04 (2H, m), 7.03 (2H*, s), 7.06 (2H*, s). 0259 d. Methyl (5-((2-ethyl-1,1-dioxo-1,2-isothiazolidin-5-yl)-(tert-butyl-dimethylsilanyloxy)-methyl)-3-methoxycarbonylmethyl-2-methoxymethoxy-phenyl)acetate (26) 0260 Ozone gas was passed through a solution of 25 (3.90 g, 7.65 mmol) in dichloromethane (100 ml) and methanol (20 ml) at 78 C. until the color of the solution turned to blue. To the reaction mixture, triethylphosphite (3.94 ml, 23 mmol) was added, and the mixture was slowly warmed to room temperature. The reaction mixture was concentrated, and the residue was added with t-butanol (40 ml), H2O (10 ml), 2-methyl-2-butene (8.1 ml, 76.5 mmol) and NaH2PO4 (2.31 g, 15.3 mmol). NaClO2 (3.50 g, 30.6 mmol) was then slowly added to the mixture at room temperature. After stirring overnight, the mixture was added with hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated. The resultant residue was added with ethyl acetate, and excess amount of an ether solution of diazomethane was dropwise added to the mixture under ice-cooling. The reaction mixture was concentrated and purified by column chromatography on silica gel to yield 2.187 g (50%) of 26. 1H NMR (CDCl3) : 0.23 (3H*, s), 0.21 (3H*, s), 0.09 (3H*, s), 0.12 (3H*, s), 0.84 (9H*, s), 0.86 (9H*, s), 1.19 (3H*, t, J7.2 Hz), 1.34 (3H*, t, J7.2 Hz), 1.62-2.58 (2H, m), 2.90-3.96 (14H, m), 4.85-5.13 (7H, m), 7.16 (2H*, s), 7.21 (2H*, s). 0261 e. Methyl 2-(5-((2-ethyl-1,1-dioxo-1,2-isothiazolidin-5-yl)-(tert-butyl-dimethylsilanyloxy)-methyl)-3-(1-methoxycarbonyl-1-methyl-ethyl)-2-methoxymethoxy-phenyl)-2-methyl-propionate (27a and 27b) 0262 A solution of 26 (4.54 g, 7.91 mmol) and MeI (3.95 ml, 63.3 mmol) in DMF (25 ml) was slowly and dropwise added to a suspension of NaH (60% in mineral oil, 1.26 g, 31.6 mmol) (n-hexane wash) in DMF (5 ml) under ice-cooling. After stirring overnight at room temperature, the reaction mixture was added with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed to obtain a residue (3.90 g). To this residue, THF (40 ml) was added, and LiHMDS (1.0 M in THF) (14.25 ml, 14.25 mmol) was dropwise added over 10 minutes under ice-cooling. After stirring for another 45 minutes, the mixture was added with MeI (3.24 ml, 51.8 mmol) and warmed to room temperature. After stirring for 1.5 hours at room temperature, the mixture was added with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel to yield 2.50 g (48%) of the titled compound as a mixture of diastereomers ((27a) less polar, 1.08 g, (27b) more polar 1.42 g). 0263 1H NMR (CDCl3) (27a): 0.20 (3H, s), 0.11 (3H, s), 0.88 (9H, s), 1.22 (3H, t, J7.2 Hz), 1.53 (6H, s), 1.55 (6H, s), 2.44-2.60 (2H, m), 2.92-3.40 (5H, m), 3.49 (3H, s), 3.64 (6H, s), 4.78 (2H, ABq, J4.5, 6.6 Hz), 5.18 (1H, d, J4.8 Hz), 7.28 (2H, s). 0264 1H NMR (CDCl3) (27b): 0.23 (3H, s), 0.12 (3H, s), 0.82 (9H, s), 1.21 (3H, t, J7.2 Hz), 1.53 (6H, s), 1.58 (6H, s), 1.70-1.89 (2H, m), 2.94-3.67 (14H, m), 4.77 (2H, s), 4.80-4.92 (1H, m), 7.23 (2H, s). 0265 f. Methyl 2-(5-((2-ethyl-1,1-dioxo-1,2-isothiazolidin-5-yl)-hydroxy-methyl)-3,3-dimethyl-2-oxo-2,3-dihydro-benzofuran-7-yl)-2-methyl-propionate (28) 0266 To a solution of 27a (416 mg, 066 mmol) in methanol (6 ml), 4N HCl/dioxane (6 ml) was added under ice-cooling, and the mixture was stirred for 2 hours at room temperature. After the reaction mixture was concentrated, the mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried, and concentrated. The residue was purified by column chromatography on silica gel to yield 207 mg (71%) of 28. 1H NMR (CDCl3) : 1.27 (3H, t, J7.2 Hz), 1.49 (6H, s), 1.61 (6H, s), 1.97-2.10 (1H, m), 2.46-2.61 (1H, m), 3.02-3.80 (8H, m), 5.49 (1H, brs), 7.17 (1H, s), 7.20 (1H, s). 0267 g. Methyl 2-(5-(2-ethyl-1,1-dioxo-1,2-isothazolidin-5-ylidenemethyl)-3,3-dimethyl-2-oxo-2,3-dihydro-benzofuran-7-yl)-2-methyl-propionate (29) 0268 To a solution of 28 (318 mg, 0.724 mmol) and Ph3P (569 mg, 2.17 mmol) in THF (5 ml), DEAD (0.171 ml, 1.09 mmol) was slowly added under ice-cooling. After stirring for 1 hour, the reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel to yield 183 mg (60%) of 29. Mp.116-120 C. (colorless powder). 1H NMR (CDCl3) : 1.30 (3H, t, J7.2 Hz), 1.51 (6H, s), 1.63 (6H, s), 3.10-3.22 (4H, m), 3.31 (2H, t, J6.3 Hz), 7.15 (1H, d, J1.8 Hz), 7.26-7.29 (2H, m). 0269 h. 2-(5-(2-Ethyl-1,1-dioxo-1,2-isothiazolidin-5-ylidenemethyl)-2-hydroxy-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-2-methyl-propionic acid (30) 0270 2N KOH (1.5 ml) was added to a solution of 29 (19 mg, 0.0364 mmol) in methanol (2 ml), and the mixture was allowed to stand overnight at room temperature. The reaction mixture was concentrated, acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and after dryness, the solvent was removed in vacuo. The residue was added with dichloromethane (1 ml), cooled to 78 C., and slowly and dropwise added with DIBAL (0.93 M in n-hexane) (0.31 ml, 0.182 mmol). After 5 minutes, a saturated aqueous ammonium chloride solution was added to quench the reaction, diluted hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and concentrated. The residue was purified by preparative TLC to yield 5.9 mg (32%) of 30. 1H NMR (d6-aceton) : 1.23 (3H, t, J7.3 Hz), 1.29 (6H, br), 1.57 (6H, s), 3.06 (2H, q, J7.3 Hz), 3.19 (2H, td, J6.5, 2.6 Hz), 3.31 (2H, t, J6.5 Hz), 5.66 (1H, s), 6.71 (1H, br), 7.12 (1H, t, J2.6 Hz), 7.27 (1H, d, J1.6 Hz), 7.34 (1H, d, J1.6 Hz). 0271 i. 5-(2-Ethyl-1,1-dioxo-1,2-isothiazolidin-5-ylidenemethyl)-7-(2-hydroxy-1,1-dimethyl-ethyl)-3,3-dimethyl-2,3-dihydro-benzofuran-2-ol (31) To a solution of 29 (56 mg, 0.133 mmol) in hexane (1 ml) and dichloromethane (1 ml) at 78 C., DIBAL (0.93 M) (0.64 ml, 0.595 mmol) was slowly added. The mixture was stirred for another 1 hour under the same conditions. The reaction mixture was added with diluted hydrochloric acid, warmed to room temperature, and stirred for another 15 minutes at room temperature. The resultant product was extracted with ethyl acetate, washed with water, saturated sodium bicarbonate, and saturated brine, dried, and concentrated. The residue was purified by column chromatography over silica gel to yield 31 mg (59%) of 31 as amorphous solid. Mp.78-82 C. 1H NMR (d6-aceton) : 1.23 (3H, t, J7.3 Hz), 1.26 (3H, brs), 1.34 (3H, brs), 1.36 (6H, s), 3.05 (2H, q, J7.3 Hz), 3.19 (2H, m), 3.31 (2H, t, J6.4 Hz), 3.59 (2H, t, J5.6 Hz), 3.76 (2H, m), 5.66 (1H, s), 6.27 (1H, br), 7.11 (1H, t, J2.7 Hz), 7.26 (1H, d, J1.8 Hz), 7.36 (1H, d, J1.8 Hz).

Example 20272

0273 a. Benzoic-acid 2-(3-(2-benzoyloxy-1,1-dimethyl-ethyl)-5-((tert-butyl-dimethyl-silanyloxy)-(2-ethyl-1,1-dioxo-1,2-isothiazolidin-5-yl)-methyl)-2-methoxymethoxy-phenyl)-2-methyl-propyl Ester (32) 0274 To a solution of 27b (529 mg, 0.84 mmol) in THF (8 ml), LiBH4 (146 mg, 6.72 mmol) was added, and the mixture was refluxed for 5 hours. The reaction mixture was added with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was dried and purified by column chromatography on silica gel to yield 309 mg of diol. This diol (141 mg, 0.246 mmol) was benzoylated according to a conventional method to give 145 mg (39% for 2 steps) of 32. 1H NMR (CDCl3) : 0.27 (3H, s), 0.10 (3H, s), 0.82 (9H, s), 1.46 (3H, t, J7.2 Hz), 1.49 (12H, s), 2.60-3.32 (7H, m), 3.64 (3H, s), 4.62 (4H, ABq, J11, 25 Hz), 4.81 (1H, d, J9.3 Hz), 4.95 (2H, s), 7.26-7.87 (12H, m). 0275 b. 4-(2-Ethyl-1,1-dioxo-1,2-isothiazolidin-5-ylidenemethyl)-2,6-bis-(2-benzoyloxy-1,1,dimethyl-ethyl)-phenol (33) 0276 To a solution of 32 (45 mg, 0.0575 mmol) in methanol (1 ml), 4N HCl/dioxane (1 ml) was added under ice-cooling, and the mixture was warmed to room temperature and stirred for 2 hours. The mixture was treated in the manner as described above, and benzene (1 ml) and catalytic amount of p-TsOH were added to the residue, and the mixture was refluxed for 3 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and concentrated. The residue was purified by preparative TLC to yield 12 mg (34%) of 33. 1H NMR (CDCl3) : 1.27 (3H, t, J7.5 Hz), 1.54 (12H, s), 3.02 (2H, td, J7.2, 2.7 Hz), 3.14 (2H, q, J7.5 Hz), 3.18 (2H, t, J7.2 Hz), 4.60 (4H, s), 7.24 (1H, t, J2.7 Hz), 7.31 (2H, s), 7.38-7.93 (10H, m). 0277 c. 4-(2-Ethyl-1,1-dioxo-1,2-isothiazolidin-5-ylidenemethyl)-2,6-bis-(2-hydroxy-1,1,dimethyl-ethyl)-phenol (34) 0278 A solution of 33 (12 mg, 0.0198 mmol) in dichloromethane (1 ml) was cooled to 78 C., and DIBAL (0.93 M) (0.107 ml, 0.099 mmol) was slowly added. After 5 minutes, the mixture was added with diluted hydrochloric acid, warmed to room temperature and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried, and the solvent was removed in vacuo. The residue was purified by preparative TLC to give 8.1 mg (quant) of 34. 1H NMR (d6-aceton) : 1.23 (3H, t, J7.3 HJz), 1.42 (12H, s), 3.04 (2H, q, J7.5 Hz), 3.18 (2H, td, J6.6, 2.6 Hz), 3.31 (2H, t, J6.6 Hz), 3.82 (4H, s), 6.99 (1H, brs), 7.08 (1H, t, J2.6 Hz), 7.39 (2H, s).

Example 30279

0280 a. Compound 38 0281 Using N-(4-methoxybenzyl)-1,2-isothiazolin-1,1-dioxide, 38 was prepared according to the synthesis of 28. 0282 b. Methyl 2-(5-(2-(4-methoxy-benzyl)-1,1-dioxo-1,2-isothazolidin-5-ylidenemethyl)-3,3-dimethyl-2-oxo-2,3-dihydro-benzofuran-7-yl)-2-methyl-propionate (39) 0283 To a solution of 38 (125 mg, 0.235 mmol) and Ph3P (123 mg, 0.47 mmol) in THF (3 ml), DEAD (0.056 ml, 0.353 mmol) was slowly added under ice-cooling. After stirring for 1 hour, the reaction mixture was concentrated, and the residue was purified by silica gel chromatography to yield 110 mg (92%) of 39. 1H NMR (CDCl3) : 1.26 (3H, t, J7.2 Hz), 1.50 (6H, s), 1.61 (6H, s), 3.02-3.18 (4H, m), 3.71 (3H, s), 3.81 (3H, s), 4.18 (2H, s), 6.87-6.90 (2H, m), 7.14 (1H, d, J1.8 Hz), 7.26-7.33 (4H, m). 0284 c. 2-(5-(1,1-Dioxo-1,2-isothiazolidin-5-ylidenemethyl)-2-hydroxy-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-2-methyl-propionic Acid (41) 0285 To a solution of 39 (63 mg, 0.160 mmol) in methanol (4 ml), 3N KOH (2 ml) was added and the mixture was allowed to stand overnight at room temperature. The reaction mixture was concentrated, acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was removed in vacuo. The residue was added with dichloromethane (2 ml), cooled to 78 C., and dropwise and slowly added with DIBAL (0.93 M in n-hexane) (0.85 ml, 0.79 mmol). After 5 minutes, the mixture was added with diluted hydrochloric acid to quench the reaction and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and concentrated. The residue was purified by preparative TLC to give 38 mg (63%) of 41. 1H NMR (d6-aceton) : 1.29 (6H, br), 1.57 (6H, s), 3.24 (2H, td, J6.7, 2.5 Hz), 3.46 (2H, t, J7.1 Hz), 5.67 (1H, s), 5.88 (12H, t, 53 (1H, br), 7.13 (1H, t, J2.5 Hz), 7.32 (1H, 7.38 (1H, d, J1.5 Hz), 10.7 (1H, br).

Example 40286

0287 a. 3-tert-Butyl-2-methoxymethoxy-toluene (43) 0288 NaH (60% in mineral oil, 4.5 g, 0.12 mol) is washed twice with hexane (50 ml) and added with THF (75 ml), and the mixture was cooled to below 10 C. A solution of 2-tert-butyl-6-methylphenol 42 (16.4 g, 0.1 mol) in THF (60 ml) was then dropwise and slowly added, and the mixture was stirred for 10 minutes under the same conditions. The mixture was then dropwise added with MOMCl (9.1 ml, 0.12 mol), warmed to room temperature, and the reaction mixture was added with saturated aqueous ammonium chloride (200 ml) and ethyl acetate (200 ml). The organic layer was separated, washed sequentially with water (200 ml), 1.5N NaOH (200 ml), water (100 ml), and saturated brine (200 ml), and dried. The solvent was removed in vacuo to give 20.5 g (98.6%) of 43 as colorless oil. 0289 b. 7-tert-Butyl-2(3H)-benzofuranone (44) 0290 A solution of 43 (3.0 g, 14.4 mmol) and TMEDA (2.6 ml, 17.3 mmol) in THF (40 ml) was cooled to 50 C., and dropwise and slowly added with sec-BuLi (1.3 M in cyclohexane, 13.3 ml, 17.3 mmol). The reaction mixture was warmed to 30 C., and then cooled again to 60 C., and dry ice was added to the mixture. The reaction mixture was warmed to room temperature over 1 hour, added with waster (50 ml) and ethyl acetate (50 ml). The aqueous layer was separated, acidified with 2N HCl to pH 3-4, and extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml) and saturated brine (50 ml), and dried. The solvent was removed in vacuo. The residue was dissolved in toluene (50 ml), added with p-TsOH.H2O (250 mg), and heated to reflux for 15 minutes. The reaction mixture was cooled to room temperature and poured into an aqueous diluted sodium bicarbonate solution (60 ml). The organic layer was separated and washed with saturated brine (60 ml). After drying, the solvent was removed in vacuo, and the residue was purified by column chromatography to yield 1.02 g (37%) of 44. 1H NMR (CDCl3) : 1.40 (9H, s, tBu), 3.71 (2H, s, CH2), 7.02-7.27 (3H, m, 3ArH). 0291 c. 7-tert-Butyl-3,3-dimethyl-2(3H)-benzofuranone (45) 0292 A solution of 44 (300 mg, 1.577 mmol), CH3I (0.29 ml, 4.73 mmol) and 18-Crown-6 (104 mg, 0.39 mmol) in THF (20 ml) was cooled to 50 C., and t-BuOK (389 mg, 3.47 mmol) was slowly added, and the mixture was stirred for 1 hour. The mixture was warmed to room temperature and stirred for another 1 hour. The reaction mixture was added with saturated aqueous ammonium chloride (30 ml) and extracted with ethyl acetate (30 ml). The organic layer was washed with water (30 ml), and saturated brine (30 ml), and dried. The solvent was removed in vacuo, and the residue was purified by column chromatography to yield 241 mg (70%) of 45. 1H NMR (CDCl3) : 1.41 (9H, s, tBu), 1.50 (6H, s, 2CH3), 7.03-7.26 (3H, m, 3ArH). 0293 d. 2-tert-Butyl-6-(2-hydroxy-1,1-dimethylethyl)phenol (46) 0294 A solution of 45 (235 mg, 1.077 mmol) in ether (5 ml) was dropwise added, with stirring and ice-cooling, to a suspension of LiAlH4 (49 mg, 1.29 mmol) in ether (5 ml). After washing a container of the solution with ether (5 ml), the washing was added to the mixture, which was warmed to room temperature and stirred for 45 minutes. The reaction mixture was added with ethyl acetate (1 ml) and 3 ml of a mixture of water and saturated ammonium chloride (1:1), and stirred for 30 minutes. Resultant slurry was removed by filtration through celite, and the filtrate was concentrated to obtain 253 mg (quant) of 46. 1H NMR (CDCl3) : 1.42 (9H, s, tBu), 1.44 (6H, s, 2CH3), 3.81 (2H, s, CH2), 6.75-7.23 (3H, m, 3ArH), 9.20 (1H, br s, phonemic-OH). 0295 e. 4-Bromo-2-tert-butyl-6-(2-hydroxy-1,1-dimethylethyl)phenol (47) 0296 To a solution of 46 (1.297 g, 5.83 mmol) in dichloromethane (20 ml), Py.HBr3 (1.86 g, 5.83 mmol) was added all at once, with stirring and ice-cooling, and the mixture was stirred for 30 minutes. Water (30 ml) was added to the reaction mixture. The organic layer was separated and washed with water (30 ml). After drying, the solvent was removed in vacuo, and the residue was purified by column chromatography to yield 1.346 g (76%) of 47. 1H NMR (CDCl3) : 1.39 (9H, s, tBu), 1.41 (6H, s, 2CH3), 3.79 (2H, s, CH2), 7.20 (1H, d, J2.4 Hz, ArH), 7.27 (1H, d, J2.4 Hz, ArH), 9.45 (1H, br s, phonemic-OH). 0297 f. 4-Bromo-2-tert-butyl-6-(2-methoxymethoxy-1,1-dimetylethyl)phenyl Methoxymethyl Ether (48) 0298 48 (930 mg, 56.9%) was prepared from 47 (1.264 g, 4.20 mmol), MOMCl (0.96 ml, 12.6 mmol) and NaH (402 mg, 10.5 mmol). 1H NMR (CDCl3) : 1.41 (9H, s, tBu), 1.42 (6H, s, 2CH3), 3.31, 3.63 (each 3H, s, CH3), 3.79 (2H, s, CH2), 4.59, 4.89 (each 2H, s, CH2), 7.36 (1H, d, J2.8 Hz, ArH), 7.38 (1H, d, J2.8 Hz, ArH) 0299 g. 3-tert-Butyl-4-methoxymethoxy-5-(2-methoxymethoxy-1,1-dimethylethyl)benzaldehyde (49) 0300 A solution of 48 (925 mg, 2.38 mmol) in THF (20 ml) was cooled to 50 C., and t-BuLi (1.7 M in pentane, 3.08 ml, 5.24 mmol) was dropwise added to the solution while maintaining the temperature below 40 C. After completion of the addition, the mixture was stirred at this temperature, and DMF (0.12 ml) in THF (5 ml) was added. The mixture was warmed slowly to room temperature. Aqueous solution of saturated ammonium chloride (50 ml) was added, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated brine (50 ml), and after dryness, the solvent was removed in vacuo. The residue was purified by column chromatography to yield 669 mg (83.1%) of 49 as colorless oil. 1H NMR (CDCl3) : 1.47 (9H, s, tBu), 1.48 (6H, s, 2CH3), 3.29, 3.66 (each 3H, s, CH3), 3.84 (2H, s, CH2), 4.60, 4.95 (each 2H, s, CH2), 7.81 (1H, d, J2.2 Hz, ArH), 7.84 (1H, d, J2.2 Hz, ArH), 9.92 (1H, s, CHO). 0301 h. (E)-2-Ethyl-5-3-tert-butyl-4-hydroxy-5-(2-hydroxy-1,1-dimethylethyl)benzylidene-1,2-isothiazolidie-1,1-dioxide (51) 0302 Aldol adduct 50 (868 mg, 91.3%) was obtained as colorless oil from 49 (660 mg, 1.95 mmol) and N-Ethyl-1,2-isothiazolidine-1,1-dioxide (305.5 mg, 2.05 mmol). To a solution of this adduct 50 (790 mg, 1.62 mmol) in methanol (6 ml), about 10N HCl/MeOH (2 ml) was added, and the mixture was stirred at room temperature for 30 minutes and at 50 C. for 30 minutes. The reaction mixture was cooled to room temperature, and aqueous saturated sodium bicarbonate (50 ml) was added. The mixture was extracted with ethyl acetate (50 ml), and the organic layer was washed with saturated brine. After dryness, the solvent was removed in vacuo. Resultant residue-was dissolved in toluene (35 ml). p-TsOH.H2O (50 mg) was added, and the mixture was heated to reflux for 10 minutes. The reaction mixture was cooled to room temperature, adsorbed to a small amount of silica gel, which was eluted with ethyl acetate (150 ml). The solvent was removed in vacuo, and the resultant residue was purified by column chromatography to yield 556 mg (90%) of 51 as colorless crystal. M.p. 152-155 C. IR (KBr) cm1: 3411, 3140, 2965, 1642, 1594, 1436, 1291, 1266, 1143. 0303 1H NMR (CDCl3) : 1.28 (3H, t, J7.2 Hz, CH3), 1.41 (9H, s, tBu), 1.43 (6H, s, 2CH3), 2.95 (1H, t, J3.8 Hz, alcoholic-OH), 3.07-3.33 (6H, m, 2CH2, CH2), 3.81 (2H, d, J3.8 Hz, CH2), 7.17 (1H, d, J2.0 Hz, ArH), 7.23 (1H, t, J2.0 Hz, vinyl-H), 7.28 (1H, d, J2.8 Hz, ArH), 9.92 (1H, s, phenolic-OH). Elementary analysis for C20H31NO4S: Calcd: C, 62.96; H, 8.19; N, 3.67; S, 8.40. Found: C, 62.86; H, 8.19; N, 3.70; S, 8.30. 0304 i. (E)-5-(7-tert-Butyl-3,3-dimethyl-2,3-dihydrobenzofuran-5-ylmethylene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide (52) 0305 A mixture of 51 (125 mg, 0.328 mmol), MsCl (30 l, 0.394 mmol), triethylamine (114 l, 0.82 mmol) and dichloromethane (10 ml) was stirred for 30 minutes under ice-cooling. The mixture was added with saturated brine (30 ml) and extracted with dichloromethane (30 ml). The organic layer was separated, and after dryness, the solvent was removed in vacuo. The residue was purified by column chromatography to yield 81 mg (68.1%) of 52. M.p. 104-106 C. IR (KBr) cm1: 3436, 2963, 2871, 1642, 1602, 1453, 1288, 1151. 1H NMR (CDCl3) : 1.29 (3H, t, J7.2 Hz, CH3), 1.33 (6H, s, 2CH3), 1.35 (9H, s, tBu), 3.06-3.33 (6H, m, 2CH2, CH2), 4.28 (2H, s, CH2), 7.01 (1H, d, J1.6 Hz, ArH), 7.15 (1H, d, J1.6 Hz, ArH), 7.25 (1H, t, J2.4 Hz, vinyl-H). Elementary analysis for C20H29NO3S: calcd: C, 66.08; H, 8.04; N, 3.85; S, 8.82. Found: C, 66.14; H, 8.07; N, 3.82; S, 8.74. 0306 The compound of the invention of formula Ia, as prepared in the above Preparation 15, was evaluated in vivo experiments for its usefulness as an antirheumatic agent, as an osteoclast formation inhibiting agent, as a nitrogen monoxide production inhibiting agent, and as a transcription factor NFB suppressing agent.

Example 5 0307 Antirheumatic Effect 0308 1. Inhibitory Activity Against the Production of Cytokines 0309 Cytokines are associated with production of proteases, collagenases, adhesion factors and the like, which are responsible for articular tissue destruction. Therefore, such articular tissue destruction could be suppressed by inhibition of cytokine production. One of these cytokines, IL-6, was used to evaluate the inhibitory activity of Compound Ia against the production of cytokine in the following manner. 0310 Method0311 A neutrophil fraction from human peripheral blood was prepared, and 10 g/mL of LPS (lipopolysaccharide) and Compound Ia were added to the fraction, and the mixture was then incubated for 16-18 hours. IL-6 was measured by RIA (radio immuno assay). 0312 Result0313 Compound Ia inhibited the IL-6 production from neutrophil (IC50: 20 M) and inhibited the IL-6 production from synovial membrane cells of RA (rheumatic arthritis) patients (IC50: 10 M). Either of these inhibitory activities was greater than Tenidap, a comparative drug (Table 1). 1TABLE 1Inhibitory Activity Against IL-6 ProductionIC50 (M)synovial membranecompoundneutrophilcells from RA patientCompound Ia2010Tenidap50>50Indomethacinnd>50nd: not determined

0314 2. Inhibitory Effect Against Rat Adjuvant Arthritis 0315 A rat adjuvant arthritis model, which is commonly used in an in vivo evaluation for antirheumatic agents, was employed in this evaluation. To prepare an arthritis model, heat-killed cells of Mycobacterium butyricum (Difco) were suspended in mineral oil, and a rat was intradermally injected with 0.05 mL of 1% solution of the suspension at the plantar of left hind leg. 0316 (i) Inhibitory Effect Against Articular Swelling 0317 Method0318 Using the above arthritis model, Compound Ia was administered to the animal for 22 days after injection of the adjuvant, and the articular swelling was measured from time to time to evaluate the prophylactic inhibitory effect. On the other hand, the curative effect was evaluated by administering Compound Ia to animals from Day 15 to Day 25 after injection of the adjuvant and measuring the articular swelling in injected and non-injected legs. Inhibitory and curative effects were expressed by effective dose for 30% inhibition (ED30). 0319 Result0320 The results are graphically shown in FIG. 1 which shows the change in volume of the adjuvant-injected or non-injected leg. Compound Ia inhibited the articular swelling both in the adjuvant-injected and non-injected legs, and dose-dependent and significant inhibitory effect was observed particularly in the adjuvant-injected leg at a dose of 0.3 mg/kg/day or more. On the other hand, as for the curative effect, dose-dependent and significant inhibitory effect was observed at a dose of 3 mg/kg/day or more. 0321 ED30 values for prophylactic and curative effects of Compound Ia and the comparative drugs are shown in Table 2 below. 2TABLE 2Inhibitory Effect Against Adjuvant Articular SwellingED30 (mg/kg/day) (95% confidence limits)compoundprophylactic effectcurative effectCompound Ia0.88 (0.52-1.31)2.6 (1.3-6.4)Tenidap0.98 (0.52-1.56)4.9 (2.4-23.0)Cyclosporin A2.40 (1.90-3.00)4.7 (1.9-7.6)Bucillamine>50>50

0322 (ii) Inhibitory Effect Against Articular Destruction 0323 Method0324 The right and left hind legs of the arthritis rats used in the above experiments were radiographed using a soft X-ray radiation and evaluated by the X-ray observation score for the bone destruction in the arthrosis. The effects were numerically evaluated by grading the articular destruction from 0 to 3 (0: normal; 1: low degree of articular and bone destruction; 2: medium degree of articular and bone destruction, and neogenesis of cartilage; 3: strong articular and bone destruction), and the efficacy in the drug-administered group was determined in comparison with the vehicle-administered group according to Wilcoxon U-test (*p<0.05, **p<0.01)(FIG. 2). 0325 Result0326 Compound Ia exhibited dose-dependent and significant inhibitory effect against the articular destruction at a dose of 3 mg/kg/day or more in the adjuvant-injected leg and at a dose of 1 mg/kg/day or more in the non-injected leg. The inhibitory effect of the comparative drug, Tenidap, was comparable to that of Compound Ia in the adjuvant-injected leg, while the effect was lower than that of Compound Ia in the non-injected leg, although the drug exhibited significant inhibitory effect at a dose of 3 mg/kg/day. On the other hand, Cyclosporin A exhibited significant inhibitory effect at a dose of 10 mg/kg/day both in the adjuvant-injected and non-injected legs (FIG. 3). 0327 (iii) Repressive Effect on the IL-6 Level in Articular Tissue 0328 Method0329 Another adjuvant arthritis model animal was prepared apart from the above experiments, and a compound was orally administered to the animal for 18 days after the adjuvant injection. The non-injected leg was then amputated under anesthetization, epidermis of the amputated leg was ablated, the leg was frozen in liquid nitrogen, and the arthrosis part was crushed by a crushing machine. To a measured quantity of the crushed arthrosis, 3 mL of ice-cold PBS was added and homogenized with a homogenizer under ice-cooling. The resultant homogenate was centrifuged at 4 C. for 20 minutes at 3,000 rpm to collect the supernatant, which was then passed through a 0.45 um filter to prepare a sample. The sample and MH60 BSF2 cells (derived from mouse, require IL-6) were incubated on a 96-well plate under defined conditions, and the absorbance was measured at two wave lengths of 540 nm and 690 nm. The IL-6 level in the sample was calculated based on the standard curve prepared using a recombinant human IL-6. The results were shown using meanstandard error of the data of seven animals, and significance test was performed according to Dunnett-t test ( p<0.01: vs. normal group; ** p<0.01: vs. vehicle group). 0330 Result0331 The IL-6 level in the articular tissue of the adjuvant arthritis rats (Veh.) was 44.2 g/g tissue, indicating remarkable increase of IL-6 level compared to that of normal rats (Nor.). Compound Ia exhibited dose-dependent and significant inhibitory effect at a dose of 3 mg/kg/day or more against the increase of the IL-6 level in the articular tissue of pathologic animals. Tenidap and Bucillamine also exhibited significant inhibitory effect at a dose of 10 mg/kg/day, and their efficacies were comparable to that of Compound Ia. Cyclosporin A (CsA) at a dose of 20 mg/kg/day almost completely inhibited the increase of the IL-6 level (FIG. 4). 0332 3. Inhibitory Effect Against Bone Destruction in Spontaneous Rheumatic Model Animal NZB/KN Mouse 0333 Method0334 To male NZB/KN mice, in which a human RA-like pathology arises spontaneously due to their immunologically abnormal background, was orally administered Compound Ia once in a day (five times a week) for six months beginning at two-month-age. The mice which reached six month old (some were eight month old) were full-length radiographed under anesthetization and predetermined conditions using a soft X-ray generator (OM-55, Omic). According to the method of Nakamura, et. al. Arthritis. Rheum., 34, 171-179 (1991), the number of the lesions observed in the bones and articular regions in the whole body were counted on the basis of the soft X-ray radiographed films, and the total number of the observed lesions were defined as the number of the bone disorders in the animal. The results were shown using meanstandard deviation, and significance test was performed according to Dunnett-t test (*p<0.05, ** p<0.01: vs. vehicle group). 0335 Result0336 Compound Ia exhibited significant improving effect on the bone-articular lesions at a dose of 10 mg/kg/day or more. As for the comparative drugs, Tenidap (Ten) and Cyclosporin A (CsA), which were each administered at a dose of 30 mg/kg/day, Cyclosporin A exhibited significant inhibitory effect while Tenidap was not effective. On the other hand, Indomethacin at a dose of 2 mg/kg/day exhibited no inhibitory effect but significant enhancing effect on the bone destruction (FIG. 5). 0337 4. Effect on MRL/l Mouse Blood Acute Phase Protein (Serum Amyloid Protein: SAP) 0338 Method0339 To MRL/l male mice known as a lupus mouse in which a human RA-like pathology spontaneously arises, Compound Ia was orally administered five times a week (twice a week for Predonisolone) for 13 weeks. After the last administration of the compound, blood was collected under anesthetization, and the serum was used for SAP measurement. SAP has been used as a marker for rheumatism. A 96-well plate was coated with rabbit anti-mouse SAP serum, and the serum to be tested was then added to the plate and incubated for 2 hours. After addition of sheep anti-mouse SAP serum, a rabbit anti-sheep IgG antibody labeled with alkaline phosphatase and then a substrate were added to the plate, and OD of developed color was measured at 405 nm. The results were shown using meanstandard error, and significance test of the results was performed according to Dunnett-t test (*p<0.05, **p<0.01: vs. vehicle group). 0340 Result0341 The groups which received Compound Ia at a dose of 2-50 mg/kg/day exhibited repressive tendency in a dose-dependent manner, and the dose of 50 mg/kg/day gave significant results. Significant inhibitory effects were also observed in the groups which received comparative drugs, Lobenzarit (Lob.) at a dose of 25 mg/kg/day and Predonisolone (Pred.) at a dose of 10 mg/kg/day. However, the groups which received Tenidap (Ten.) at a dose of 10 mg/kg/day, Indomethacin (Ind.) at a dose of 1 mg/kg/day and Bucillamine (Buc.) at a dose of 10 or 25 mg/kg/day gave no significant results although they exhibited suppressive tendency (FIG. 6).

Example 6 0342 Inhibitory Effect Against Osteoclast Formation 0343 Inhibitory Effect Against Enhanced Formation of Osteoclast in Mouse Myeloblast 0344 Method0345 It has been known that the enhanced formation of osteoclast is induced in the mouse myeloblast culture by addition of IL-1 and such effect is derived from PGE2 production through COX-2 induction. In order to determine inhibitory effect of the compounds against such effect, myeloblasts were collected from a ddY male mice, plated in a 48-well plate at 1106/well and incubated. After culturing for six days in an -MEM medium containing 10% fetal bovine serum, to which 2.5 ng/mL of human IL-1 and a predetermined concentration of the compounds were added, PGE2 level in the supernatant was measured by RIA kit. On the other hand, cells adhering on the plate were immobilized, and an activity staining of tartaric acid resistant acid phosphatase (TRAP), which is a marker enzyme for osteoclast, was conducted, whereby the number of TRAP positive cells having multinucleate (N>3) per well was counted as osteoclast. 0346 Resuit0347 Test compounds were added to the above culture and assayed for their inhibitory activity against the PGE2 production due to IL-1 stimulation and the enhanced formation of osteoclast. The results were shown in terms of IC50 (Table 3). Compound Ia exhibited stronger inhibition as compared with Tenidap and Indomethacin. The inhibition of Compound Ia was greater than that of N-2-(cyclohexyloxy)-4-nitrophenyl-methanesulfoneamide, a selective COX-2 inhibitor. 3TABLE 3Inhibitory Activity Against Enhanced Formation ofOsteoclast and PGE2 ProductionIC50 (M)Inhibition ofInhibition ofOsteoclastPGE2compoundFormationProductionCompound Ia0.00130.00021Tenidap0.0630.0017Indomethacin0.0320.0064N-2-(cyclohexyloxy)nitro-0.0240.0042phenymethanesulfoneamide

Example 7 0348 Inhibitory Effect Against Nitrogen Monoxide Production 0349 1. Inhibitory Activity Against NO Production from Activated Macrophage (M) 0350 Method0351 To BALB/c male mice was intraperitoneally administered 2 mL of a thioglycolate solution, and induced activated M were collected after four days and used as NO producing cells. The cells were adjusted to 2106 cells/mL and plated onto a 96-well microtiter plate at 2105 cells/100 L/well. 10 L of 1 g/mL of Compound Ia and LPS (lipopolysaccharide) were added thereto and incubated at 37 C. under 5% CO2 for 24 hours. 75 L of the supernatant obtained after incubation and 75 L of Griess reagent were incubated, and NO20 in the form of sodium nitrite was measured to determine the amount of NO in the supernatant. 0352 Result0353 Compound Ia at 0.8-12.5 M inhibited NO production in a dose-dependent manner in the above assay system. The inhibitory activity of Compound Ia against NO production was greater than those of the comparative agents, Tenidap and Indomethacin (Table 4). 4TABLE 4Inhibitory Activity Against NO Production In MouseActivated MacrophageNO2- Production (M/2 105 cells)Medium<0.1Medium LPS28.3 2.29MCompound IaTenidapIndomethacin0.827.3 0.9431.5 1.0529.5 0.683.112.3 2.50**33.1 0.7527.9 1.9112.5<1.0***36.2 0.91*23.9 2.4950<1.0***19.7 0.96**14.9 3.02**100<1.0***3.3 1.99***3.0 2.41***IC50 (M)3.075.060.0Values in the table are mean standard error of independent experiments. *p <0.05, **p <0.01, ***p <0.001: Student t-test

0354 2. Suppressive Effect on Blood NO Level 0355 Method0356 An adjuvant arthritis model was prepared in the same manner as above, and the compounds were orally administered to the animals for 28 days beginning on the day before the adjuvant injection. Blood was then collected under anesthetization and the serum was ultracentrifuged. The supernatant was ultrafiltrated to prepare a sample for NOx (nitritenitrate) measurement. Serum NOx level was determined by the measurement of optical density at 550 nm using the improved absorptiometry by Griess Tracy, W. R. Tse, J., and Carter, G., (1995), J. Pharmacol. Exp. Ther., 272, 1011-1015. The results were shown using meanstandard error of the data of eight samples, and significance test was performed according to Dunnett's t-test (p<0.01: vs. normal group; *p<0.05, **p<0.01: vs. vehicle group). 0357 Result0358 Serum NOx level in the arthritis-maturing phase on 28th day after adjuvant administration was increased by about three times as compared with the normal level. Compound Ia at a dose of 3 mg/kg/day or more exhibited the dose-dependent and significant inhibitory effect on the increase of blood NOx level in this pathological animal. As for the comparative drug, Tenidap, significant effect was observed at 10 mg/kg/day, while mere inhibitory tendency was observed at 30 mg/kg/day. Thus, the inhibitory effect of Tenidap was lower than that of Compound Ia. Indomethacin (Ind) at 1 mg/kg/day and Dexamethazon (Dex) at 0.3 mg/kg/day also exhibited significant inhibitory effect (FIG. 7).

Example 8 0359 Suppressive Effect on Transcription Factor NFB Suppressive Activity on Transcription Factor NFB 0360 Method0361 A recombinant plasmid (pGV-B.HIV-1LTR), in which HIV-1 (AIDS) virus promoter LTR containing two NFB binding sites is ligated to upstream of firefly luciferase gene, was constructed, and the DNA was purified. This plasmid DNA was introduced by electroporation into a Jurkat cell, a human T cell leukemic cell line, and the cell was cultured for 48 hours. Subsequently, phytohemagglutinin (PHA, 0.5%), phorbol ester (TPA (12-O-tetradecanoylphorbol 13-acetate), 25 ng/mL), and a predetermined concentration of the test compound were added thereto to allow to react for 2 hours, and the cells were harvested, and the luciferase activity in the cellular extract was measured. 0362 Result0363 Compound Ia inhibited luciferase activity at 5-50 M in a dose-dependent manner (Table 5, Experiment-1). The comparative drugs, Tenidap and Lobenzarit, inhibited the activity at 20-50 M and at 500 M, respectively, while their efficacies were lower than that of Compound Ia. No inhibitory effect was observed for Bucillamine even at 500 M (Table 5, Experiment-1 and Experiment-2). 5TABLE 5Suppressive Activity on Transcription Factor NFBluciferase activity (%)luciferase activity (%)Experiment-mean Experiment-mean 1MNstandard error2MNstandard errorcontrol226.9 1.5control244.1 9.4TPA-PHA4100.0 2.5TPA-PHA2100.0 4.6Compound5482.2 8.3Compound20286.4 1.9Ia10479.6 5.4Ia50175.120454.6 4.3100261.1 3.950453.5 5.9Lobenzarit202112.6 1.9Tenidap5494.0 14.01002100.6 2.710494.4 7.2500270.6 4.920375.6 19.1Bucillamine20196.050469.3 17.1100296.1 6.25002101.0 0.8

0364 Values in the table are meanstandard error of independent experiments in terms of relative luciferase activity.

Example 90365

6Formulations1) GranulesCompound of the invention20 mgLactose250 mgCorn starch115 mgHydroxypropylcellulose115 mg

0366 Above materials are granulated in a conventional wet process to obtain granules.

EFFECT OF THE INVENTION 0367 The compounds of the present invention have an inhibitory effect against articular bone destruction and the like in a rheumatic model animal, and yet the inhibitory effect against the production of IL-6 and acute phase proteins such as serum amyloid. Accordingly, the compounds of the invention are useful as an antirheumatic agent for prevention and/or treatment of rheumatoid arthritis. 0368 Also, since the compounds of the present invention have an inhibitory effect against the enhanced formation of osteoclast in mouse myeloblasts, they are useful as an preventing and/or treating agent for bone metabolic disorders such as rheumatoid arthritis, osteoarthritis and osteoporosis and the like. 0369 Further, the compounds of the present invention are useful for prevention and/or treatment of rheumatoid arthritis and osteoarthritis since they exhibit an inhibitory effect against NO production in macrophage which has received an inflammatory stimulus and NO production in an inflammatory pathological model animal. Due to inhibitory effect against NO production, the compounds of the invention would be useful for prevention and/or treatment of atherosclerosis, ischemic heart and brain disease, Alzheimer disease, diabetes, endotoxin shock, sepsis, ulcerative colitis and the like. 0370 Furthermore, since the compounds of the invention exhibit a suppressive effect on NFB in human cells, they are useful for prevention and/or treatment of chronic articular rheumatism. Based on the suppressive effect on NFB, the compounds of the invention would also be useful for systemic lupus erythematosus, Behcet's disease, ulcerative colitis, atherosclerosis, endotoxin shock, sepsis, cytomegalovirus pneumonia, adenovirus cold, AIDS and the like.