JPH06211819A - Benzylidene derivative - Google Patents

Abstract

PURPOSE:To obtain a new benzylidene derivative capable of extremely strongly suppressing production of PGE2 and simultaneously suppressing production of cytokinins such as LTbeta4 and IL-1 and expecting antiinflammatory action. CONSTITUTION:A compound of the formula {A is CH2 or CH2CH2; B is direct bond, CH2, CHOH, CO or O, or A and B together form CH=CH; D is N or CH; R<1> and R<2> are H, lower alkyl or lower alkoxy; R<3> is H, lower alkyl, cycloalkyl, lower alkoxy, arylalkyloxy, heteroarylalkyloxy, lower alkylcarbonyl, arylcarbonyl, (substituted)carbamoyl or (CH2)n-R<4> [R<4> is H, OH, amino, aryl, etc.; (n) is 0-3]}, e.g. (E)-2-ethyl-5-(3,5-di-butyl-4-hydroxy)benzylidene-1,2- isothiazolidine-1,1-dioxide.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel benzylidene derivative having an anti-inflammatory effect.

[0002]

BACKGROUND OF THE INVENTION Conventionally, non-steroidal anti-inflammatory drugs, like lysozyme chloride, have been effective in improving early symptoms of rheumatism and acute inflammation, but progress in bone destruction and the like. However, it is not effective in improving chronic rheumatic symptoms or treating osteoarthritis, and has a problem that it has a strong gastric ulcer-inducing action. Recently, it has been revealed that leukotriene (LT), which is a metabolite of arachidonic acid metabolic pathway by 5-lipoxygenase, particularly LTB ₄ is an important mediator of inflammatory reaction. In addition, it has been suggested that interleukin-1 (IL-1), which is a kind of cytokine, is involved in inflammation, particularly, it is greatly involved in chronic rheumatism.
From the above background, compounds that inhibit the production of both LTB ₄ and IL-1 are considered promising as anti-inflammatory agents. Since such a compound can be expected to be effective not only for acute inflammation but also for chronic inflammation such as rheumatoid arthritis, it is more useful than conventional non-steroidal anti-inflammatory agents.

Such an anti-inflammatory agent is disclosed in JP-A-58-79.
944, JP-A-61-257967, and JP-A-62-1952.
No. 42977, JP-A-1-305028, JP-A-2-
4729, JP-A-2-256645, JP-A-2-2
Various compounds are disclosed in Japanese Patent No. 70865, Japanese Patent Publication No. 1-503782, and the like. However, in order to obtain a compound that has few side effects such as gastric disorders and is effective in treating chronic inflammation, prostaglandin E ₂ (PG
There is a need to provide compounds having an inhibitory action on the production of inflammatory mediators such as E ₂ ), LTB ₄ and IL-1.

[0004]

The present inventors have found that certain benzylidene derivatives extremely strongly suppress the production of PGE ₂ and at the same time suppress the production of cytokines such as LTB ₄ and IL-1. The present invention has been completed.

That is, the present invention provides formula I:

[Chemical 2] [In the formula, A is —CH ₂ — or —CH ₂ CH ₂ —; B is
Or represents a bond or _{-CH 2 -, - CHOH -,} - CO
-, -O-, or A and B together form -CH = C
H-may be formed; D is> N- or> C
H-; R ¹ and R ² are each independently hydrogen, lower alkyl or lower alkoxy; R ³ is hydrogen, lower alkyl, cycloalkyl, lower alkoxy; arylalkyloxy, heteroarylalkyloxy, lower alkylcarbonyl, arylcarbonyl, substituted or unsubstituted carbamoyl or _{formula,: - (CH 2) n} -R 4 ( wherein, R ⁴ is hydrogen, hydroxy, substituted or unsubstituted amino, aryl, heteroaryl, hydroxycarbonyl or lower alkyloxycarbonyl Carbonyl; n is 0 to 3
And represents a group represented by) and represents a group represented by].

Representative compounds of the compound I of the present invention include, for example, compounds in which the sulfur-containing heterocyclic moiety is represented by the following formula.

[Chemical 3] (In the formula, D represents> N- or> CH-.) The preferred compound of the formula I is a compound whose sulfur-containing heterocyclic moiety is represented by the following formula.

[0007]

[Chemical 4] As is clear from the above formula, Compound I can exist in both (E)-and (Z) -configurations. Therefore, unless otherwise specified, the term compound I as used herein is intended to include (E) -type and (Z) -type compatible isomers.

Each term used in this specification will be described below. “Lower alkyl” means a C ₁ -C ₈ linear or branched alkyl group, such as 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,
Octyl is exemplified. Of these, C ₁ -C ₄ linear or branched alkyl is preferable. The most preferred group is methyl or ethyl. “Lower alkoxy” means straight chain or branched alkyloxy having 1 to 6 carbon atoms,
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, t-hexyloxy and the like are exemplified. . Of these, C ₁ -C ₃ alkoxy is preferable. The most preferred group is methoshiki. "Cycloalkyl" has 3 to 7 carbon atoms.
And cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Of these, C ₃ -C ₅ cycloalkyl is preferable.

"Aryl" means unsubstituted or substituted phenyl or naphthyl, and the substituent is
Examples thereof include halogen, lower alkoxy, lower alkyl, and nitro group, which may have one or more. For example,
Phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-nitrophenyl, 3,4-dichlorophenyl,
3,4-dimethoxyphenyl, 3,4-dinitrophenyl, 1-naphthyl, 2-naphthyl and the like can be mentioned. The "arylalkyloxy" is the above lower alkoxy group substituted with the above aryl group, and is benzyloxy, 4-
Chlorobenzyloxy, 4-methoxybenzyloxy,
3,4-dichlorobenzyloxy, 3,4-dimethoxybenzyloxy, 4-nitrobenzyloxy, 2-phenylethyloxy, 2- (4-chlorophenyl) ethyloxy, 2- (4-methoxyphenyl) ethyloxy,
Examples are 1-naphthylmethyloxy and 2-naphthylmethyloxy. Of these, benzyloxy is preferable. The “heteroaryl” is a group having 1-4 hetero atoms, and examples thereof include pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl and tetrazolyl. Preferred heterocycles for this invention are pyridyl, thiazolyl, oxazolyl, imidazolyl. The most preferred group is pyridyl. "Halogen" means fluorine, chlorine, bromine,
Examples include iodine. The "heteroarylalkyloxy" is the above alkoxy group substituted with the above heteroaryl group, and is 2-pyridylmethyloxy, 3-pyridylmethyloxy, 4-pyridylmethyloxy, 2-imidazolylmethyloxy, 4-imidazolylmethyl. Oxy, 2-thiazolylmethyloxy, 4-thiazolylmethyloxy and the like are exemplified. "Lower alkylcarbonyl"
Is acetyl, propionyl, butyryl, valeroyl,
Hexayl, heptanoyl, octanoyl and the like are exemplified. "Arylcarbonyl" means benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl, 3,4-dichlorobenzoyl, 3,4-dimethoxybenzoyl, 3,4-dinitrobenzoyl, 1-
Examples include naphthoyl and 2-naphthoyl. In the term "substituted or unsubstituted carbamoyl", the substituent is exemplified by lower alkyl, lower alkoxy, hydroxy, cycloalkyl, arylalkyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, cycloalkyloxy, arylalkyloxy,
These may have any one or more substitutions on the N atom. Of these, lower alkyl, lower alkoxy and hydroxy are preferable. For example, N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-hydroxycarbamoyl, N-
Methyl-N-hydroxycarbamoyl, N-methoxycarbamoyl, N-methoxy-N-methylcarbamoyl,
Examples thereof include N-ethylcarbamoyl, N, N-diethylcarbamoyl, N-ethyl-N-hydroxycarbamoyl, N-propylcarbamoyl, N, N-dipropylcarbamoyl, and N-propyl-N-hydroxycarbamoyl.

"Halogen" includes fluorine, chlorine, bromine and iodine. "Lower alkyloxycarbonyl" means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, te.
Examples include rt-butoxycarbonyl and the like. “Substituted amino” means mono- or di-substituted amino, and examples of the substituent include the above lower alkyl and arylalkyl.

The compound of the present invention showed an excellent in vitro inhibitory effect on PGE ₂ , LTB ₄ and IL-1 production as compared with the control compound E5110 and indomethacin, as described in Experimental Examples described later. In addition, it was shown to have an edema inhibitory effect in vivo and a low gastric mucosal damaging effect, and it was revealed that it may be an excellent non-steroidal anti-inflammatory drug. The benzylidene derivative of the present invention is a novel compound and can be produced, for example, by the method 1 described below, but these do not limit the present invention in any way.

(1)

[Chemical 5] (In the formula, A, B, D, R ¹ , R ² and R ³ are as defined above, and R ⁵ represents hydrogen or a hydroxy protecting group.)

Of the starting materials for the above reaction, the sulfur-containing heterocyclic compound 4 can be produced, for example, according to the following reaction formula.

[Chemical 6] (In the formula, R ³ is as defined above)

[0014] 3-chlorosulfonyl chloride 1 get 'is reacted with amine 2 sulfonamide intermediate 3'. The reaction is carried out in the presence of a base (A), if necessary, as a solvent, ether, chloroform, methylene chloride, dichloroethane, tetrahydrofuran, dimethoxyethane, diethoxyethane, benzene, toluene, xylene, ethyl acetate, methyl acetate, etc. Perform using a solvent.
The amine (R ³ NH ₂ ) may be the hydrochloride salt. Examples of the base (A) used as necessary include alkali metal salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate, pyridine, 4-N, N-dimethylaminopyridine (DMAP) triethylamine, diisobutylethylamine, 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU), 1,4-diazabicyclo
Examples are organic bases such as [2,2,2] octane (DABCO). When an alkali metal salt is used, it is preferable to add a phase transfer catalyst if necessary. As the phase transfer catalyst, quaternary ammonium salts such as N-benzyltrimethylammonium salt and tetrabutylammonium salt are preferable. The reaction of the sulfonamide intermediate 3 ′ to the sulfur-containing heterocyclic compound 4 ′ can be carried out in the presence of a base (B) in the same solvent as described above, but an anhydrous solvent such as dimethyl sulfoxide or dimethylformamide is used. desirable. As the base (B), sodium hydride or lithium hydride can be used in addition to the above bases.

[0015] Alternatively, 'a, the sulfonamide intermediate 3' Compound 1 without isolating the, it is also possible to at once obtain a sulfur-containing heterocyclic compound 4 '. for that purpose,
For example a suitable solvent to reaction with the compound 1 'with amine 2,
Performed in the presence of 2 equivalents of base. The solvent and base are selected from the above examples, but the base is sodium hydride,
It is particularly preferable to use dimethylformamide as the solvent.

[0016]

[Chemical 7] Alternatively, the target sulfur-containing heterocyclic compound 4 ′ can be obtained from commercially available γ-saltone 5 ′ (see Reference Example). That is, the compound 5 ′ is reacted with an amine (R ³ NH ₂ ) and then a dehydrating agent is acted on. The reaction operation can be carried out without using a solvent, but may be carried out in the above-mentioned solvent, if necessary. As the dehydrating agent, commonly used agents such as phosphorus oxychloride, thionyl chloride, phosphorus pentachloride and phosphorus pentaoxide can be used, but phosphorus oxychloride is particularly preferable.

R ^{5 of} compound 6 represents hydrogen or a hydroxy protecting group. Methoxymethyl as a hydroxy protecting group,
Mention may be made of methoxyethoxymethyl, trimethylsilyl, tert-butyldimethylsilyl. R ⁵ is preferably a hydroxy protecting group, especially a methoxymethyl group. The aldol reaction of compound 6 with compound 4 obtained above is carried out in the presence of a base (C) in a suitable solvent. As the base (C), n-butyllithium, sec-butyllithium, tert-
Examples thereof include organic lithium salts such as butyllithium, phenyllithium, lithium diisopropylamide, lithium diethylamide and lithium hexamethyldisilazane, and alkali metal bases such as sodium hydride and potassium tert-butoxide. Particularly preferred is lithium diisopropylamide or lithium hexamethyldisilazane. Examples of the reaction solvent include ether solvents such as diethyl ether, tetrahydrofuran (THF), dimethoxyethane and diethoxyethane, and hydrocarbon solvents such as n-hexane and cyclohexane. It is desirable to coexist with a reagent that serves as a ligand of metallic lithium, for example, tetramethylethylenediamine, hexamethylphosphoramide, etc., if necessary. The reaction temperature is −80 ° C. to + 50 ° C., but it is preferably carried out on the low temperature side.

The aldol adduct 7 is treated with a compound in the presence of an acid.
Convert to 8 and 9 . Examples of the acid include organic acids such as trifluoroacetic acid, p-toluenesulfonic acid and camphorsulfonic acid, and inorganic acids such as sulfuric acid and hydrochloric acid. Further, ordinary dehydrating agents such as thionyl chloride, methanesulfonyl chloride, aluminum chloride, phosphorus oxychloride, phosphorus pentachloride and the like may be used. The reaction is preferably carried out in an aromatic hydrocarbon such as benzene, toluene or xylene, a halogenated hydrocarbon such as chloroform, dichloromethane, dichloroethane or the like, an ether solvent such as tetrahydrofuran, dimethoxyethane or diethoxyethane, under heating.

(2)

[Chemical 8]

The base (C) in the above formula has the same meaning as defined above. Y represents an N-protecting group, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-
Methoxybenzyl, 3,4-dimethoxybenzyl, 4-
Examples thereof include a nitrobenzyl group. The conditions for the aldol reaction are the same as in the case of (1) above. Aldol adduct
Examples of dehydration and deprotection agents used for conversion of 7 into 10a and 10b include p-toluenesulfonic acid, trifluoroacetic acid outer aluminum chloride, and titanium tetrachloride.
The conditions such as reaction solvent and temperature are the same as in the case of (1).
The mixture of (E) and (Z) was deprotected and D was> N in formula I.
-, and R ³ is a hydrogen 10a, obtain 10b.

(3)

[Chemical 9]

In this reaction, the compound of the present invention 10 obtained in the above (2), wherein D is> N- and R ³ is hydrogen in the formula I.
The desired substituent R ³ is added to to obtain various derivatives. R ³
When -X is an alkylating agent, examples of the base (D) used include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, alkali metal salts such as lithium hydroxide, or pyridine, Examples thereof include organic bases such as triethylamine and diisopropylethylamine. The alkylation is preferably carried out using sodium hydroxide or potassium carbonate with a suitable quaternary ammonium salt being shared as a phase transfer catalyst.

When R ³ X is an acylating agent, it is preferable to use an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or diisopropylethylamine as the base (D). When R ³ X is a carbamoylating agent or an alkoxycarbonylating agent, it is preferable to use an organic lithium base such as n-butyllithium, lithium hexamethyldisilazane or lithium diisopropylamide as the base (D). However, it is not necessary to limit to these, and an organic base such as pyridine, triethylamine, diisopropylethylamine or the above-mentioned alkali metal salt may be used as well.

(4)

[Chemical 10]

Compounds 8 and 9 were debenzylated to form formula I
In which D is> N- and R ³ is a hydroxyl group 11
a and 11b are obtained. Debenzylation is performed using a deprotecting agent. For deprotection, hydrogenation in the presence of a palladium carbon or platinum oxide catalyst or a Lewis acid such as aluminum chloride or titanium tetrachloride is used, and if necessary, anisole, 2,6-di-t
It can be carried out in the coexistence of ert-butylphenol and the like. As the reaction solvent, in addition to halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane,
Nitromethane, benzene, toluene, xylene and the like can also be used. Although the methods described in (1), (2) and (3) above are generally applicable to the preparation of compound I of the present invention,
A specific example thereof is shown in Example 1-35 described later.

Further, the compound I of the present invention has the following formula:

[Chemical 11] The compound represented by the formula (1) is subjected to ring closure by reacting with a commonly used dehydrating agent such as ethyl chlorocarbonate in the presence of triethylamine.

[Chemical 12] Can also be produced by a method comprising obtaining the compound 8 of Examples of the dehydrating agent also include ethyl chloroformate, phosphorus oxychloride, thionyl chloride, DCC (dicyclohexylcarbodiimide) and the like. This alternative method can also be generally applied to the production of the compound I of the present invention by appropriately selecting the starting materials and the reaction conditions. The compound I of the present invention can be administered orally or parenterally as an anti-inflammatory agent. When administered orally, the compound of the present invention may be formulated in a usual formulation such as tablets, powders, granules,
It may be used in any of the dosage forms of solid preparations such as capsules; water preparations; oily suspensions; or liquid preparations such as syrups or elixirs. In the case of parenteral administration, the compound of the present invention can be used as an aqueous or oily suspension injection or an external preparation. In its preparation, any of the conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents and the like can be used, and other additives such as preservatives and stabilizers. It may contain an agent or the like. The dose of the compound of the present invention is, administration method, patient age,
Although it varies depending on the body weight, condition and type of disease, it is usually 10 to 500 per day orally for adults.
mg, preferably 50 to 100 mg, or parenterally, 1 to 250 mg, preferably 5 to 10 mg per day, which may be administered in 1 to 5 divided doses. Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited thereto. The abbreviations used in the examples have the following meanings. LDA: lithium diisopropylamide MOM: methoxymethyl p-TsOH: paratoluenesulfonic acid THF: tetrahydrofuran DMF: N, N-dimethylformamide HMPA: hexamethylphosphoramide LiHMDS: lithium hexamethyldisilazane DBU: 1,8-diazabicyclo [5 , 4,0] Undec-7-ene DIBAL: diisobutylaluminum hydride

【Example】

[Chemical 13]

Production Example 1 (R ³ = Et) N-Ethyl-1,2-isothiazolidine-1,1-dioxy
Cid (4a) 3-chloropropylsulfonyl chloride 1 (6.1 gr,
Ethylamine in a solution of ether (34.5 mmol) (25 ml)
(70% aqueous solution, 4.4 gr, 68.3 mmol) was added dropwise under ice cooling and stirring, and after the addition was completed in about 15 minutes, the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and benzene 1 was added to the residue.
After adding 00 ml and distilling off the solvent under reduced pressure, 150 ml of ether was added to the residue and the insoluble matter was filtered off, and ether was distilled off under reduced pressure to obtain crude N-ethyl-3-chloropropylsulfonamide intermediate Body 3a was obtained as colorless crystals with mp 30-32 ° C. Yield 6.96 gr (-100%). This intermediate 3a
Sodium hydride (60% oily, 1.52 gr, 38.0 mmol) was gradually added to a THF solution (50 ml) of (6.96 gr, 34.5 mmol) under ice-cooling stirring, and the addition was completed in 15 minutes. did. Then stirring was continued for 30 minutes at room temperature. Ether (50 ml) was added to the reaction solution, the insoluble matter was filtered off, and the solvent was evaporated under reduced pressure to obtain the target compound 4a as a pale yellow oily matter. Yield 4.93 gr (96%) IR (CHCl ₃ ) cm ^-1 : 3018,2976,2868,14
52,1306,1220,1179,1129,1015. NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.4Hz, C
_{H 3), 2.28-2.42 (2H,} m, CH 2), 3.10 (2H,
q, J = 7.4 Hz, CH ₂ ), 3.15 (2 H, t, J = 7.6 Hz,
_{CH 2), 3.22-3.29 (2H,} m, CH 2)

Production Example 2 (R ³ = Me) N-methyl-1,2-isothiazolidine-1,1-dioxy
Sid (4b) 3-chloropropylsulfonyl chloride 1 (16.8 g
r, 94.9 mmol), methylamine hydrochloride (13.5 gr, 20
0 mmol) and potassium carbonate (27.6 gr, 200 mmol) were sequentially added to ethyl acetate (500 ml), and N-benzyltrimethylammonium chloride (about 200 mg) was added to the mixture.
Was added and stirred at room temperature for 2 hours, and then the reaction solution was dried over anhydrous sodium sulfate. The reaction solution was filtered through a small amount of silica gel and concentrated under reduced pressure to obtain crude N-methyl-3-chloropropylsulfonamide intermediate 3b as a pale yellow oil. Yield 12gr (74%)

Intermediate 3b (11.79 gr, 68.69 mmo)
l) in benzene solution (300 ml) DBU (10.79 ml,
72.12 mM) was added and the mixture was stirred at room temperature for 24 hours, filtered through a small amount of silica gel, and the solvent was evaporated under reduced pressure to obtain the target compound 4b as a colorless solid having an mp of 36-40 ° C. Yield 7.0 gr (75%) IR (CHCl ₃ ) cm ^-1 : 3016,1451,1307,12
18,1187,1127. NMR (CDCl ₃ ) δ: 2.27-2.42 (2H, m, CH ₂ ),
2.69 (3H, s, CH ₃ ), 3.11-3.20 (2H, m, CH
₂ ), 3.22 (2H, t, J = 6.8Hz, CH ₂ ).

Production Example 3 (R ³ = CH ₂ CH (CH ₃ ) ₂ ) N-isobutyl-1,2-isothiazolidine-1,1-di
Oxide (4c) 3-chloropropylsulfonyl chloride 1 (7.08 g
r, 40mmol), isobutylamine (7.3gr, 100mmo
l) and sodium hydrogen carbonate (3.36 gr, 40 mmol) were sequentially added to a mixed solution of ethyl acetate (200 ml) and water (20 ml), and N-benzyltrimethylammonium chloride (about 100 mg) was further added to the mixture at room temperature for 3 hours. After stirring, the reaction solution was treated in the same manner as in Preparation Example 2 to mp the crude N-isobutyl-3-chloropropylsulfonamide intermediate 3c.
Obtained as colorless crystals at 68-69 ° C. Yield 8.19gr (9
6%). DBU (3.3 ml, 22 mmol) was added to a solution of this intermediate 3c (4.27 gr, 20 mmol) in benzene (60 ml), and the reaction solution was treated in the same manner as in Production Example 2 to obtain the target compound 4c.
Was obtained as a colorless oil. Yield 3.37 gr (95%). IR (CHCl ₃ ) cm ^-1 : 3016,2956,1465,13
04, 1226, 1131, 1024 NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.6Hz, (C
_{H 3) 2), 1.75-1.96 (} 1H, m, CH), 2.27-2.
42 (2H, m, CH ₂ ), 2.80 (2H, d, J = 7.4Hz, C
_{H 2), 3.10-3.19 (2H,} m, CH 2), 3.24 (2H,
t, J = 6.8 Hz, CH ₂ ).

Production Example 4 (R ³ = cyclopropyl) N-cyclopropyl-1,2-isothiazolidine-1,1
-Dioxide (4d) 3-chloropropylsulfonyl chloride 1 (7.08 g
r, 40mmol), cyclopropylamine (6.0gr, 105mm
ol) and sodium hydrogen carbonate (3.7 gr, 44 mmol) in a mixed solution of ether (200 ml) and water (10 ml) in the same manner as in Production Example 3 to give crude N-cyclopropyl-3-chloropropylsulfone. Amide intermediate 3d mp
Obtained as crystals at 48-49.5 ° C. Yield 8.0gr (～ 1
(00%)

The intermediate 3d (1.98 gr, 10 mmol) and DBU (1.65 ml, 11 mmol) were reacted in benzene (30 ml) in the same manner as in Production Example 2 to give the desired compound 4d as a pale yellow oil. Obtained. Yield 1.40 gr (87%) IR (CHCl ₃ ) cm ^-1 : 3016,1309,1221,11
40,1026. NMR (CDCl ₃ ) cm ⁻¹ : 0.60-0.85 (4H, m, cyclopropyl), 2.20-2.40 (2H, m, CH ₂ ), 3.15
-3.25 (3H, m, CH ₂ + CH), 3.32 (2H, t, J =
6.6 Hz, CH ₂ ).

Production Example 5 (R ³ = -CH ₂ CH ₂ CH ₃ ) Nn-propyl-1,2-isothiazolidine-1,1-
Dioxide (4e) 3-chloropropyl chloride 1 (7.08gr, 40mmo
l), n-propylamine (5.90 gr, 100 mmol), potassium carbonate (5.52 gr, 40 mmol) and a small amount of N-benzyltrimethylammonium chloride (about 100 mg) in a mixture of ether (200 ml) and water (20 ml). After stirring at room temperature for 3 hours, the mixture was treated in the same manner as in Production Example 2 to obtain crude N-.
n-Propyl-3-chloropropylsulfonamide intermediate 3e was obtained as crystals with mp 47.5-48 ° C. Yield 8.
0 gr (-100%). This intermediate 3e (2.0 gr, 10 mmol)
And DBU (1.65 ml, 11 mmol) with benzene (30 ml)
And react with the same method as in Production Example 2 to obtain the target compound 4e.
Was obtained as a pale yellow to colorless oil. Yield 1.41 gr (86
%) IR (CHCl ₃ ) cm ^-1 : 3018,2962,2868,13
04, 1224, 1130, 1019 NMR (CDCl ₃ ) δ: 0.96 (3H, t, J = 7Hz, C
_{H 3), 1.52-1.72 (2H,} m, CH 2), 2.28-2.4
_{2 (2H, m, CH 2} ), 2.94-3.04 (2H, m, CH 2),
_{3.10-3.20 (2H, m, CH 2} ), 3.25 (2H, t, J =
6.7Hz, CH ₂ )

Production Example 6 (R ³ = OCH ₃ ) N-methoxy-1,2-isothiazolidine-1,1-dio
Xide (4f) 3-chloropropylsulfonyl chloride 1 (7.08 g)
r, 40 mmol), O-methylhydroxylamine hydrochloride
(3.67gr, 40mmol), potassium carbonate (5.80gr, 42m
mol) was reacted in the same manner as in Production Example 5 to give a crude N-methoxy-3-chloropropylsulfonamide intermediate 3f.
Was obtained as a colorless to pale yellow oil. Yield 7.02gr (94
%). This intermediate 3f (6.25 gr, 33.3 mmol) was reacted with sodium hydride (60% oily, 1.47 gr, 36.7 mmol) in the same manner as in Production Example 1 to obtain the target compound 4f.
Was obtained as a colorless oil. Yield 3.70 g (73%) IR (CHCl ₃ ) cm ^-1 : 3022,1355,1249,12
22, 1165, 1138, 1035, 1011. NMR (CDCl ₃ ) δ: 2.37-2.50 (2H, m, CH ₂ ),
3.20-3.14 (2H, m, CH ₂ ), 3.50 (2H, t, J =
7.0 Hz, CH ₂ ), 3.81 (3H, s, OCH ₃ ).

Production Example 7 (R ³ = OCH ₂ C ₆ H ₅ ) N-benzyloxy-1,2-isothiazolidine-1,1
-Dioxide (4g) 3-chloropropylsulfonyl chloride 1 (30.28
gr, 0.17 mol), O-benzylhydroxylamine hydrochloride 27.3 g (0.17 mol), potassium carbonate (50 gr, 0.3
6 mol) and tetrabutylammonium sulfate (about 500 mg)
Was reacted in a mixed solution of ether (1 l) and water (100 ml) at room temperature for 24 hours, and the reaction solution was extracted with ethyl acetate. The ethyl acetate extract was subjected to silica gel column chromatography, and 3 g of crude N-benzyloxy-3-chloropropylsulfonamide intermediate was obtained as a pale yellow oil from the fraction eluted with a mixed solution of ethyl acetate-n-hexane (1: 4). I got it as a thing. Yield 18.4gr (41%)

The same procedure as in Preparation Example 1 was carried out by adding sodium hydride (60% oily, 2.94 gr, 73.4 mmol) to a THF solution (150 ml) containing 3 g (18.4 gr, 69.9 mmol) of the above intermediate. The product was subjected to silica gel column chromatography, and 4 g of the target compound (mp 52-54) was obtained from the fraction eluted from a mixed solution of ethyl acetate-n-hexane (1: 5).
Obtained as colorless crystals at 0 ° C. Yield 10.75 gr (68%) IR (CHCl ₃ ) cm ^-1 : 3022,2956,1453,13
54, 1165, 1140, 1081, 1000 NMR (CDCl ₃ ) δ: 2.30-2.48 (2H, m, CH ₂ ),
_{3.04-3.14 (2H, m, CH 2} ), 3.45 (2H, t, J =
6.9 Hz, CH ₂ ), 5.00 (2 H, s, OCH ₂ ), 7.30-
_{7.45 (5H, m, C 6} H 5).

Production Example 8 (R ³ = 4-methoxybenzyl) N- (4-methoxybenzyl-1,2-isothiazolidine
-1,1- Dioxide (4h) 3-Chloropropylsulfonyl chloride 1 (17.7g)
r, 0.1 mol), p-methoxybenzylamine (15.0 gr,
0.11 mol) and sodium hydrogen carbonate (8.4 gr, 0.1 mo)
l) was reacted in a mixed solution of ethyl acetate (400 ml) and water (40 ml) in the same manner as in Production Example 3 to give crude N- (4
-Methoxybenzyl) -3-chloropropylsulfonamide intermediate 3h was obtained as colorless crystals with mp 78 ° C-80 ° C. Yield 19.1 gr (69%) Intermediate 3h (11.11 gr, 40 mmol) and DBU (6.
6 ml, 40 mmol) in benzene (150 ml),
The same treatment as in Preparation Example 2 was carried out to give the desired compound 4h as mp 48 ° C-
Obtained as crystals at 51 ° C. Yield 8.89 gr (92%) IR (CHCl ₃ ) cm ^-1 : 3016,1612,1511,13
04, 1245, 1136, 1034 NMR (CDCl ₃ ) cm ⁻¹ : 2.20-2.38 (2H, m, C
H ₂ ), 3.09 (2H, t, J = 6.8Hz, CH ₂ ), 3.14-
3.24 (2H, m, CH ₂ ), 3.81 (3H, s, OCH ₃ ), 4.
12 (2H, s, CH ₂ ), 6.84-6.94 (2H, m, CH ₂ ),
7.22-7.32 (4H, m, 4 × aromatic-H)

Production Example 9 (R ³ = 3,4-dimethoxybenzyl) N- (3,4-dimethoxybenzyl) -1,2-isothiazo
Lysine-1,1-dioxide (4i) 3-chloropropylsulfonyl chloride 1 (8.85 g
r, 50 mmol) 3,4-dimethoxybenzylamine (9.0
ml, 60 mmol) and potassium carbonate (4.14 gr, 30 mmol) were reacted in the same manner as in Preparation Example 2 to give crude N- (3,4-
Dimethoxybenzyl) -3-chloropropylsulfonamide intermediate 3i was obtained. Yield 14.5 gr (94%). The target compound 4i was obtained from this intermediate 3i according to the method of Production example 1.
Yield 69% IR (CHCl ₃ ) cm ^-1 : 3018,1516,1307,12
62, 1225, 1155, 1138, 1027 NMR (CDCl ₃ ) δ: 2.22-2.38 (2H, m, CH ₂ ),
3.11 (2H, t, J = 6.7Hz, CH 2), 3.16-3.2
5 (2H, m, CH ₂ ), 3.88 (3H, s, OCH ₃ ), 3.89
_{(3H, s, OCH 3)} , 4.12 (2H, s, CH 2), 6.79-
6.91 (3H, m, 3 × aromatic-H)

Production Example 10 (R ³ = C ₆ H ₅ ) N-phenyl-1,2-isothiazolidine-1,1-dio
Xide (4j) 3-chloropropylsulfonyl chloride 1 (1.456)
gr, 8.23 mmol) was added dropwise to a solution of aniline (0.5 ml, 8.23 mmol) in pyridine (5 ml) at -20 ° C to -30 ° C with cooling, and the reaction solution was added after completion of the addition in about 5 minutes. 45 more at room temperature
Stir for minutes. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the fraction eluted with a mixed solution of ethyl acetate-n-hexane (1: 2) gave N-phenyl-.
3-Chloropropylsulfonamide intermediate 3j was obtained as a yellow oil. Yield 1.683 g (88%). The target compound 4j was obtained as a pale yellow solid from the intermediate 3j according to the method of Production example 1. Yield 57% IR (CHCl ₃ ) cm ^-1 : 3020,1598,1495,13
15,1139. NMR (CDCl ₃ ) δ: 2.46-2.60 (2H, m, CH ₂ ),
_{3.34-3.42 (2H, m, CH 2} ), 3.78 (2H, t, J =
6.6 Hz, CH ₂ ), 7.10-7.40 (5 H, m, C
₆ H ₅ ).

Production Example 11 (R ³ = 4-chlorophenyl) N- (4-chlorophenyl) -1,2-isothiazolidine
1,1-dioxide (4k) N- (4-chlorophenyl) -3-chloropropylsulfone was prepared by reacting 3-chloropropylsulfonyl chloride and 4-chloroaniline in pyridine in the same manner as in Production Example 10. The amide intermediate 3k was obtained. Yield 93%.
Then, this intermediate 3k was treated with D in the same manner as in Production Example 2.
It was treated with BU to give the desired compound 4k as mp 110.5-111.
Obtained as colorless crystals at 5 ° C. Yield 68% IR (KBr) cm ^-1 : 3010,2960,1595,149
_{. 3,1300,1267,1131 NMR (CDCl 3) δ} : 2.47-2.61 (2H, m, CH 2),
_{3.35-3.43 (2H, m, CH 2} ), 3.76 (2H, t, J =
_{6.4Hz, CH 2), 7.16-7.36 (} 4H, m, 4 × aromat
ic-H)

Production Example 12 (R ³ = 2-pyridyl) N- (2-pyridyl) -1,2-isothiazolidine-1,1
-Dioxide (4l) In the same manner as in Production Example 10, 3-chloropropylsulfonyl chloride was reacted with 2-aminopyridine to give N.
3 l of-(2-pyridyl) -3-chloropropylsulfonamide intermediate was obtained as a pale yellow solid. Yield 54%. Then, to a DMF solution (30 ml) of 3 l (2.138 gr, 9.11 mol) of this intermediate was added sodium hydride (60% oiliness,
(401 mg, 10 mmol), and the mixture was stirred at 85 ° C. for 30 minutes, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, ethyl acetate-n-hexane.
4 l of the target compound was obtained as a yellow solid from the fraction eluted with the (1: 1) mixture. Yield 1.806 g (100%) IR (CHCl ₃ ) cm ^-1 : 3022,1592,1473,14
34,1139. NMR (CDCl ₃ ) δ: 2.47-2.60 (2H, m, CH ₂ ),
3.43 (2H, t, J = 7.5Hz, CH ₂ ), 4.05 (2H, t,
J = 6.6 Hz, CH ₂ ), 6.88-7.02 (1 H, m, CH),
7.26-7.35 (1H, m, CH), 7.58-7.70 (1
H, m, CH), 8.33 (1H, d, J = 4.4Hz, CH)

Production Example 13 (R ³ = 3-pyridyl) N- (3-pyridyl) -1,2-isothiazolidine-1,1
-Dioxide (4m) In the same manner as in Production Example 10, 3-chloropropylsulfonyl chloride 1 (7.28g, 41.1mmol) and 3-aminopyridine (4.6gr, 49.3mmol) were added to pyridine (15ml).
To give crude N- (3-pyridyl) -3-chloropropylsulfonamide 3m intermediate as a colorless solid. Yield 4.50g (46%)

3 m of this intermediate (232 mg, 0.988 mmol)
Sodium hydride (60% oily, 4 ml) in DMF (5 ml)
The desired compound 4m was obtained as a colorless solid by treatment with 3.5 mg, 1.09 mmol) in the same manner as in Production Example 12. Yield 19
0 mg (97%) IR (CHCl ₃ ) cm ^-1 : 3022,2960,1590,14
84 (1428), 1319, 1142. NMR (CDCl ₃ ) δ: 2.53-2.67 (2H, m, CH ₂ ),
_{3.38-3.45 (2H, m, CH 2} ), 3.83 (2H, t, J =
_{6.6Hz, CH 2), 7.28-7.36 (} 1H, m, CH), 7.
73-7.79 (1H, m, CH), 8.41 (1H, d, J = 4.
6Hz, CH), 8.46 (1H, d, J = 2.4Hz, CH)

Production Example 14 (R ³ = 4-pyridyl) N- (4-pyridyl) -1,2-isothiazolidine-1,1
-Dioxide (4n) 3-chloropropylsulfonyl chloride 1 (3 ml, 2
4.7 mmol) and 4-aminopyridine (2.32 g, 24.7 mmo)
Sodium hydride (60% oil, 2.17 g, 54.3 mmol) was gradually added to a DMF solution (25 ml) of l) under ice cooling and stirring over about 5 minutes. Then, stirring was continued at 50 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the target compound 4n was obtained as a yellow solid from the fraction eluted with a methylene chloride-methanol (10: 1) mixed solution. Yield 1.294 gr (27%) IR (CHCl ₃ ) cm ^-1 : 3024,2956,1597,15
04, 1320, 1143 NMR (CDCl ₃ ) δ: 2.53-2.67 (2H, m, CH ₂ ),
3.43 (2H, t, J = 7.6Hz, CH ₂ ), 3.81 (2H, t,
J = 6.6 Hz, CH ₂ ), 7.08 (2 H, d, J = 5.4 Hz, C
H), 8.49 (2H, d, J = 5.4Hz, CH)

[0045]

[Chemical 14] Example ^{1 (R 3 = Et) (} E) -2- ethyl-5- (3,5-di -tert- butyl-4
-Hydroxy) benzylidene-1,2-isothiazolidine
-1,1-dioxide (8a) and its (Z) -isomer (9
a) While melting in ice, diisopropylamine (15.5 ml, 110.6 mm)
ol) in n-hexane solution of n-butyllithium (1.6M, 6
(9.5 ml, 111 mmol) is added dropwise with stirring over 20 minutes, and after the addition is complete, stirring is continued for 15 minutes. The reaction solution was cooled to −78 ° C., 100 ml of THF was added, and N-ethyl-1,2-
Isothiazolidine-1,1-dioxide 4a (15gr, 1
5,5-di-tert-butyl-4-methoxymethoxybenzaldehyde 6a (25 g, 90.5 mmol)
And a solution of HMPA (30 ml) in THF (70 ml) were added dropwise with stirring over 15 minutes, and then stirring was continued at the same temperature for 30 minutes. After warming the reaction solution to room temperature, cold 2N-HCl
(100 ml), extracted twice with ethyl acetate (250 ml), and the ethyl acetate layer was diluted with aqueous sodium hydrogen carbonate solution (3
(00 ml) and then saturated saline (300 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with n-hexane-ethyl acetate (4: 1 to 1: 1) for purification to obtain an aldol adduct 7a as a colorless solid. Yield 21.3gr
(55%). P-Toluenesulfonic acid hydrate was added to a toluene solution (150 ml) of this adduct 7a (8.5 gr, 19.9 mmol).
(2.49 gr, 13 mmol) was added and the mixture was heated under reflux for 30 minutes, then the reaction solution was poured into dilute aqueous sodium hydrogen carbonate solution (150 ml) and extracted twice with ethyl acetate (150 ml), and the organic layer was washed with water ( The extract was washed with 150 ml) and then with saturated saline (150 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, and the target compounds 9a and 8a were obtained sequentially from the fractions eluted with n-hexane-ethyl acetate (3: 1). Yield 8a: 2.59g
r (36%); 9a: 376 mg (7%).

8a: mp135-137 ° C. IR (KBr) cm ^-1 : 3610,3440,2970,288
0,1645,1597,1430,1290,1173,1
151, 1139. NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.2Hz, C
_{H 3), 1.45 (18H,} s, 2 × Bu t), 3.07-3.19
(4H, m, CH ₂ ), 3.28 (2H, q, J = 7.2Hz, CH ₂ ),
5.50 (1H, s, OH), 7.24-7.26 (3H, m, 2xa
. romatic-H, CH) Elemental analysis _{(C 20 H 31 NO 3 S} ) 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

9a: mp 137-138 ° C. IR (KBr) cm ^-1 : 3560,2975,1637,160
0,1431,1289,1275,1168,1150,1
111 NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.2Hz, C
H ₃ ), 1.45 (18 H, s, 2 × Bu ^t ), 3.00 (2 H, dt,
J = 2.0, 6.0 Hz ,, CH ₂ ), 3.15 (2H, q, J = 7.
2Hz, CH ₂ ), 3.25 (2H, t, J = 6.0Hz, CH ₂ ),
5.47 (1H, s, OH), 6.73 (1H, t, J = 2.0Hz,
. CH), 7.52 (2H, s, 2 × aromatic-H) Elemental analysis _{(C 20 H 31 NO 3 S} ) Calcd: C, 65.71; H, 8.55 ; N, 3.83 S, 8.
77 Found: C, 65.68; H, 8.43; N, 3.61; S, 8.
66

Example 2 (R ³ = CH ₃ ) (E) -2-methyl-5- (3,5-di-tert-butyl-4)
-Hydroxy) benzylidene-1,2-isothiazolidine
-1,1-dioside (8b) and its (Z) -isomer (9b) were prepared according to the same method as in Example 1 for compound 6a (3.34 gr,
12 mmol) and N-methyl-1,2-isothiazolidine-
Adduct 7b was obtained by aldol reaction with 1,1-dioxide 4b (1.35 gr, 10 mmol). Yield 1.65gr (40
%). A solution of this adduct 7b (1.60 gr, 3.87 mmol) in toluene (30 ml) was added with p-toluenesulfonic acid hydrate (160 ml).
(mg) was added and the mixture was heated under reflux for 30 minutes. The reaction product was subjected to silica gel column chromatography, and target compounds 8b and 9b were obtained from the fractions eluted from the n-hexane-ethyl acetate (3: 7) mixed solution. Yield 8b: 580 mg (43%);
9b: 200 mg (15%)

8b: mp 168-170 ° C IR (CHCl ₃ ) cm ^-1 : 3620,2956,1435,12
92, 1218, 1149. NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × Bu ^t ), 2.
76 (3H, s, NCH ₃ ), 3.07-3.18 (2H, m, C
H ₂ ), 3.20-3.32 (2H, m, CH ₂ ), 5.51 (1H,
s, OH), 7.23-7.29 (3H, m, 2 × aromatic-H,
CH). Elemental analysis value (C ₁₉ H ₂₉ NO ₃ S) calculated value: C, 64.92; H, 8.32; N, 3.98; S, 9.
12 Found: C, 64.62; H, 8.31; N, 3.95; S, 9.
149b: mp 152-163 ° C IR (CHCl ₃ ) cm ^-1 : 3622,2956,1433,12
93,1241,1160,1010 NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × Bu ^t ), 2.
75 (3H, s, NCH ₃ ), 2.95-3.05 (2H, m, C
H ₂ ), 3.16-3.26 (2H, m, CH ₂ ), 5.49 (1H,
s, OH) .6.75 (1H, t, J = 2.2Hz, CH), 7.58
(2H, s, 2 × aromatic-H) Elemental analysis value (C ₁₉ H ₂₉ NO ₃ S) Calculated value: C, 64.92; H, 8.32; N, 3.98; S, 9.
12 Found: C, 64.61; H, 8.29; N, 3.95; S, 9.
07

Example 3 (R ³ = CH ₂ CH (CH ₃ ) ₂ ) (E) -2-isobutyl-5- (3,5-di-tert-butyl)
-4-Hydroxy) benzylidene-1,2-isothiazoli
Zin-1,1-dioxide (8c) Compound 6a (2.78 gr, 1) was prepared according to the same method as Example 1.
0 mmol) and N-isobutyl-1,2-isothiazolidine-1,1-dioxide 4c (1.95 gr, 11 mmol) with aldol reaction to give adduct 6c. Yield 3.67gr (8
1%) This adduct 7c (3.60 gr, 7.9 mmol) was used in Example 1
P-toluenesulfonic acid hydrate (36
It was treated with 0 mg) and toluene (50 ml). The product was subjected to silica gel column chromatography, and the target compound 8c was obtained from the fraction eluted with a n-hexane-ethyl acetate (1: 3) mixed solution. Yield 1.30gr (42%), mp167-1
70 ° C IR (CHCl ₃ ) cm ^-1 : 3620,2956,1646,14
35,1289,1240,1148,1081 NMR (CDCl ₃ ) δ: 0.97 (6H, d, J = 6.4Hz, (C
_{H 3) 2), 1.45 (} 18H, s, 2 × Bu t), 1.81-2.0
2 (1H, m, CH), 2.87 (2H, d, J = 7.4Hz, C
H ₂ ), 3.06-3.18 (2H, m, CH ₂ ), 3.22-3.3
3 (2H, m, CH ₂ ), 5.50 (1H, s, OH), 7.23-7.
27 (3H, m, 2 × aromatic-H, CH) Elemental analysis value (C ₂₂ H ₃₅ NO ₃ S) Calculated value: 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

Example 4 (R ³ = cyclopropyl) (E) -2-cyclopropyl-5- (3,5-di-tert-butane
Cyl-4-hydroxy) benzylidene-1,2-isothia
Zolidine-1,1-dioxide (8d) According to the same method as in Example 1, compound 6a (2.67 gr,
9.6 mmol) and N-cyclopropyl-1,2-isothiazolidine-1,1-dioxide 4d (1.29 gr, 8.0 mmo)
Aldol reaction with l) gave adduct 7d. Yield 3.09 gr (88%). This adduct 7d (3.0 g, 7 mmol) was added to p-toluenesulfonic acid hydrate (30 ml) in toluene (50 ml).
0 mg). The reaction product was purified in the same manner as in Example 3 to obtain the target compound 8d. Yield 1.03gr
(40%). mp202-204 ° C IR (CHCl ₃ ) cm ^-1 : 3620,2956,1434,12
97,1237,1145 NMR (CDCl ₃ ) δ: 0.68-0.90 (4H, m, 2 × C
H ₂ ), 1.44 (18H, s, 2 × Bu ^t ), 2.28-2.40
(1H, m, CH), 3.08 (2H, dt, J = 2.6,6.7Hz,
CH ₂ ), 3.36 (2H, t, J = 6.7Hz, CH ₂ ), 5.51
(1H, s, OH), 7.20-7.25 (3H, m, 2 × aromatic
-H, CH), Elemental analysis _{(C 21 H 31 NO 3 S} ) 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

Example 5 (R ³ = CH ₂ CH ₂ CH ₃ ) (E) -2-n-propyl-5- (3,5-di-tert-butyl)
Lu-4-hydroxy) benzylidene-1,2-isothiazo
Lysine-1,1-dioxide (8e) and its (Z) -isomer
(9e) In the same manner as in Example 1, compound 6a (2.78 gr,
10 mmol) and Nn-propyl-1,2-isothiazolidine-1,1-dioxide 4e (1.35 gr, 8.27 mmol)
The adduct 7e was obtained by the aldol reaction with. Yield 1.5
gr (41%). This adduct 7e was treated with p-toluenesulfonic acid hydrate (400 mg) in the same manner as in Example 1. The reaction product was subjected to silica gel column chromatography, and the target compounds 8e and 9e were obtained from the fractions eluted with a n-hexane-ethyl acetate (1: 4) mixed solution. Yield 8e:
810 mg (26%); 9e: 120 mg (3.8%)

8e: mp 181-183 ° C. IR (CHCl ₃ ) cm ^-1 : 3616,2954,1435,12
89,1146 NMR (CDCl ₃ ) cm ^-1 : 0.98 (3H, t, J = 7.4Hz,
_{CH 3), 1.45 (18H,} s, 2 × Bu t), 1.57-1.7
8 (2H, m, CH ₂ ), 2.98-3.20 (4H, m, 2 × C
_{H 2), 3.22-3.34 (2H,} m, CH 2), 5.50 (1H,
s, OH), 7.23-7.27 (3H, m, 2 × aromatic-H,
CH) Elemental analysis value (C ₂₁ H ₃₃ NO ₃ S) Calculated value: C, 66.45; H, 8.76; N, 3.69; S, 8.
45 Found: C, 66.25; H, 8.74; N, 3.70; S, 8.
339e: mp123-124.5 ° C IR (CHCl ₃ ) cm ^-1 : 3622,2958,1433,12
89, 1164 NMR (CDCl ₃ ) δ: 0.96 (3H, t, J = 7.4Hz, C
_{H 3), 1.45 (18H,} s, 2 × Bu t), 1.55-1.72
(2H, m, CH ₂ ), 2.95-3.08 (4H, m, 2 × CH ₂ ),
_{3.20-3.29 (2H, m, CH 2} ), 5.47 (1H, s, O
H), 6.74 (1H, t, J = 2.1Hz, CH), 7.57 (2
H, s, 2 × aromatic-H).

Example 6 (R ³ = OCH ₃ ) (E) -2-methoxy-5- (3,5-di-tert-butyl-
4-hydroxy) benzylidene-1,2-isothiazolidi
-1, -1, -dioxide (8f) and its (Z) -isomer (9
f) According to the method similar to Example 1, compound 6a (5.56 gr,
Aldol reaction with 20 mmol) and N-methoxy-1,2-isothiazolidine-1,1-dioxide 4f (3.32 gr, 22 mmol) gave adduct 7f. Yield 6.89gr
(80%). This adduct 7f (6.89 gr, 16 mmol) was treated with p-toluenesulfonic acid hydrate (1 gr) in toluene (100 ml) according to the same method as in Example 1. The reaction product was subjected to silica gel column chromatography, and the target compounds 8f and 9f were obtained from the fractions eluted from the n-hexane-ethyl acetate (6: 1) mixed solution. Yield 8f: 2.40gr (41
%); 9f: 500 mg (8.5%) 8f: mp 166-168 ° C IR (CHCl ₃ ) cm ^-1 : 3616,2952,1639,14
36, 1340, 1240, 1158, 1002. NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × Bu ^t ), 3.
11 (2H, dt, J = 2.8, 7.0Hz, CH ₂ ), 3.66 (2
H, t, J = 7Hz, CH ₂ ), 3.81 (3H, s, OCH ₃ ), 5.
55 (1H, s, OH), 7.25-7.35 (3H, m, 3 x arom
atic-H, CH) Elemental analysis value (C ₁₉ H ₂₉ NO ₄ S) Calculated value: C, 62.10; H, 7.95; N, 3.81; S, 8.
72 Found: C, 61.90; H, 7.88; N, 3.91; S, 8.
679f; mp173-176 ° C IR (CHCl ₃ ) cm ^-1 : 3616,2950,1431,13
41,1240,1155,1010 NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × Bu ^t ), 3.
12 (2H, dt, J = 2.2, 6.8Hz, CH ₂ ), 3.61 (2
H, t, J = 6.8Hz, CH ₂ ), 3.61 (3H, s, OCH ₃ ),
5.49 (1H, s, OH), 7.01 (1H, t, J = 2.2Hz,
CH), 7.49 (2H, s, 2 × aromatic-H) Elemental analysis value (C ₁₉ H ₂₉ NO ₄ S × 0.4H ₂ O) Calculated value: C, 60.90; H, 8.02; N, 3.74; S, 8.
56 Found: C, 61.08; H, 7.76; N, 3.75; S, 8.
61

Example 7 (R ³ = OCH ₂ C ₆ H ₅ ) (E) -2-benzyloxy-5- (3,5-di-tert-bu
Cyl-4-hydroxy) benzylidene-1,2-isothia
Zolidine-1,1-dioxide (8 g) According to the same method as in Example 1, Compound 6a (15 gr, 54
mmol) and 4 g (10.23 gr, 45 mmol) of N-benzyloxy-1,2-isothiazolidine-1,1-dioxide to give 7 g of adduct. Yield 15.51
gr (68%). 7g of this adduct (10.21gr, 20.2mmol)
And p-toluenesulfonic acid according to the same method as in Example 1.
Treated with (1 gr) and toluene (150 ml). The reaction product was filtered through a small amount of silica gel, and the filtrate was concentrated under reduced pressure to obtain 8 g of the target compound. Yield 5.32gr (59%) mp
134-135 ° C IR (CHCl ₃ ) cm ^-1 : 3620,2956,1639,14
36,1339,1241,1159 NMR (CDCl ₃ ) δ: 1.44 (18H, s, 2 × Bu ^t ), 3.
09 (2H, dt, J = 2.6, 6.8Hz, CH ₂ ), 3.58 (2
H, t, J = 6.8Hz, CH ₂ ), 5.02 (2H, s, OCH ₂ ),
5.53 (1H, s, OH), 7.25-7.45 (8H, m, 7xa
. romatic-H, CH) Elemental analysis _{(C 25 H 33 NO 4 S} ) Calculated: 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

Example 8 (R ³ = 4-methoxybenzyl) (E) -2- (4-methoxybenzyl) -5- (3,5-di-
tert-Butyl) benzylidene-1,2-isothiazolidine
-1,1-Dioxide (8h) and its (Z) -isomer (9h) Compound 6a (9gr, 32mmo ) according to the same method as in Example 1.
1) and N- (4-methoxybenzyl) -1,2-isothiazolidine-1,1-dioxide 4h (7.24 gr, 30 mmol) were aldol-reacted to obtain an adduct 7h. Yield 13.1
6 gr (84%). This adduct 6h (12.6gr, 24.2mmol)
Was treated with p-toluenesulfonic acid hydrate (1.3 gr) in toluene (150 ml) in the same manner as in Example 1 to obtain a mixture of the target compounds 8h and 9h. Yield 8.83 gr.

Example 9 (R ³ = 3,4-dimethoxybenzyl) (E) -2- (3,4-dimethoxybenzyl) -5- (3,5)
-Di-tert-butyl-4-hydroxy) benzylidene-
1,2-isothiazolidine-1,1-dioxide (8i) and
Its (Z) -isomer (9i) Compound 6a (5.6 gr, 20 m) was prepared according to the same method as Example 1.
mol) and N- (3,4-dimethoxy) benzyl-1,2-isothiazolidine-1,1-dioxide 4i (5.85 g, 2
Aldol reaction with 1.6 mmol) was carried out to obtain adduct 7i. Yield 9.25 g (78%). This adduct 7i (4gr, 7.3
(mmol) to carry out dehydration and deprotection reactions in the same manner as in Example 1 to obtain a mixture of the target compounds 8i and 9i. Yield 2.5 gr.

Example 10 (R ³ = C ₆ H ₅ ) (E) -2-phenyl-5- (3,5-di-tert-butyl-
4-hydroxy) benzylidene-1,2-isothiazolidi
-1,1-dioxide (8j) and its (Z) -isomer (9
j) Compound 6a (2.47 gr, 8.88 ) was prepared in the same manner as in Example 1.
mmol) and N-phenyl-1,2-isothiazolidine-
Aldol reaction with 1,1-dioxide 4j (2.19 gr, 11.10 mmol) was carried out to obtain adduct 7j. Yield 3.18
4 gr (75%). This adduct 7j (3.184g, 6.69mmo)
l) was treated with p-toluenesulfonic acid hydrate (750 mg) in toluene (100 ml) to obtain target compounds 8j and 9j.
Yield 8j: 667mg (24%); 9j: 110mg (4%)

8j: mp 195-196 ° C. IR (KBr) cm ^-1 : 3560,3520,2960,163
6,1593,1492,1430,1295,1268,1
105,1092 IR (CDCl ₃ ) δ: 1.47 (18H, s, 2 × Bu ^t ), 3.3
1 (2H, dt, J = 2.6, 6.6Hz, CH ₂ ), 3.80 (2H,
t, J = 6.6 Hz, CH ₂ ), 5.54 (1 H, s, OH), 7.17
-7.26 (2H, m, aromatic-H, CH), 7.29 (2H,
s, 2 × aromatic-H), 7.38-7.42 (4H, m, 4 × ar
. omatic-H) Elemental analysis _{(C 24 H 31 NO 3 S} × 0.1H 2 O) 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.
619j: mp172-174 ° C IR (KBr) cm ^-1 : 3540,2960,1629,159
8,1503,1435,1305,1255,1140,1
118 NMR (CDCl ₃ ) δ: 1.44 (18 H, s, 2 × Bu ^t ), 3.
17 (2H, dt, J = 2.0, 6.2Hz, CH ₂ ), 3.77 (2
H, t, J = 6.2Hz, CH 2), 5.49 (1H, s, OH), 6.
84 (1H, t, J = 2.0Hz, CH), 7.18-7.40 (5
H, m, 5 × aromatic-H), 7.59 (2H, s, 2 × aromatic
. -H) Elemental analysis _{(C 24 H 31 NO 3 S} × 0.1H 2 O) Calcd: C, 69.39; H, 7.61 ; N, 3.37; S, 7.
72 Found: C, 69.28; H, 7.56; N, 3.39; S, 7.
69

Example 11 (R ³ = 4-chlorophenyl) (E) -2- (4-chlorophenyl) -5- (3,5-di-te)
rt-Butyl-4-hydroxy) benzylidene-1,2-i
Sothiazolidine-1,1-dioxide (8k) and its (Z)
-Isomer (9k) According to the same method as in Example 1, Compound 6a (2.25 gr,
8.09 mmol) and N- (4-chlorophenyl) -1,2-
Isothiazolidine-1,1-dioxide 4k (2.34 gr,
Aldol reaction with (10.1 mmol) was carried out to obtain adduct 7k. Yield 2.54 gr (62%). This adduct 7k (2.53g
r, 4.96 mmol) was treated with p-toluenesulfonic acid hydrate (250 mg) in toluene (70 ml) to obtain target compounds 8k and 9k. Yield 8k: 859mg (39%); 9k: 263mg
(12%)

8k: mp 245-246 ° C. IR (KBr) cm ^-1 : 3560,2960,1644,159
2,1491,1430,1280,1105,1090 NMR (CDCl ₃ ) δ: 1.46 (18H, s, 2 × Bu ^t ), 3.
30 (2H, dt, J = 2.6, 6.6Hz, CH ₂ ), 3.76 (2
H, t, J = 6.6Hz, CH ₂ ), 5.55 (1H, s, OH), 7.
28 (2H, s, 2 × aromatic-H), 7.26-7.40 (5
H, m, 4 × aromatic-H, CH). Elemental analysis value (C ₂₄ H ₃₀ NO ₃ SCl) Calculated value: 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, 7.879k: mp 207-209 ° C IR (KBr) cm ^-1 : 3540,2955,1635,159
_{5,1494,1432,1300,1270,1130 NMR (CDCl 3) δ:} 1.44 (18H, s, 2 × Bu t), 3.
17 (2H, dt, J = 2.0, 6.4Hz, CH ₂ ), 3.73 (2
H, t, J = 6.4Hz, CH 2), 5.51 (1H, s, OH), 6.
86 (1H, t, J = 2.0Hz, CH), 7.34 (4H, s, 4 ×
. aromatic-H), 7.57 ( 2H, s, 2 × aromatic-H) Elemental analysis _{(C 24 H 30 NO 3 SCl} ) Calcd: C, 64.34; H, 6.75 ; N, 3 .13; S, 7.
16; Cl, 7.91 Found: C, 64.14; H, 6.80; N, 3.23; S, 7.
06, Cl, 7.95

Example 12 (R ³ = 2-pyridyl) (E) -2- (2-pyridyl) -5- (3,5-di-tert-butane)
Cyl-4-hydroxy) benzylidene-1,2-isothia
Zolidine-1,1-dioxide (8l) and its (Z) -isomerism
Body (9l) According to the same method as in Example 1, Compound 6a (208 mg,
0.75 mmol) and N- (2-pyridyl) -1,2-isothiazolidine-1,1-dioxide 41 (149 mg, 0.75 m)
Aldol reaction with (mol) gave adduct 7 l. Yield 233 mg (65%). 7 l of this adduct (231 mg, 0.485)
mmol) was treated with p-toluenesulfonic acid hydrate (60 mg) in toluene (5 ml) to obtain the target compounds 8l and 9l. Yield 8l: 96mg (48%); 9l: 19mg (9%)

8l: mp 177-179 ° C IR (KBr) cm ^-1 : 3570,2960,1646,160
0,1587,1472,1431,1300,1105,1
085 NMR (CDCl ₃ ) δ: 1.47 (18H, s, 2 × Bu ^t ), 3.
31 (2H, dt, J = 2.4, 6.8Hz, CH ₂ ), 4.08 (2
H, t, J = 6.8Hz, CH ₂ ), 5.55 (1H, s, OH), 6.
99-7.05 (1H, m, CH), 7.28 (2H, s, 2 x arom
atic-H), 7.38 (1H, t, J = 2.4Hz, Py-H),
7.55-7.74 (2H, m, 2xPy-H), 8.33-8.
36 (1H, m, Py) .. Elemental analysis value (C ₂₃ H ₃₀ N ₂ O ₃ S) Calculated value: C, 66.63; H, 7.29; N, 6.76; S, 7.
73 Found: C, 66.31; H, 7.30; N, 6.72; S, 7.
669 l: mp 198-199 ° C IR (KBr) cm ^-1 : 3550,2960,1626,159
4,1570,1470,1429,1312,1302,1
272, 1140, 1115. NMR (CDCl ₃ ) δ: 1.46 (18H, s, 2 × Bu ^t ), 3.
16 (2H, dt, J = 2.0,6.6Hz, CH ₂ ), 4.06 (2
H, t, J = 6.6Hz, CH 2), 5.51 (1H, s, OH), 6.
87 (1H, t, J = 2.0Hz, CH), 6.96-7.04 (1
H, m, Py-H), 7.58 (2H, s, 2x aromatic-H), 7.
54-7.73 (2H, m, 2xPy-H), 8.32-8.37
. (1H, m, Py- H) Elemental analysis _{(C 23 H 30 N 2 O} 3 S) Calcd: C, 66.63; H, 7.29 ; N, 6.76; S, 7.
73 Found: C, 66.40; H, 7.23; N, 6.71; S, 7.
53

Example 13 (R ³ = 3-pyridyl) (E) -2- (3-pyridyl) -5- (3,5-di-tert-butane)
Cyl-4-hydroxy) benzylidene-1,2-isothia
Zolidine-1,1-dioxide (8 m) According to the same method as in Example 1, Compound 6a (1.474 g)
r, 5.30 mmol) and N- (3-pyridyl) -1,2-isothiazolidine-1,1-dioxide 4 m (1.051 gr, 5.
Aldol reaction with 30 mmol) gave adduct 7m.
Yield 1.522 gr (60%). This adduct 7m (1.522g)
r, 3.19 mmol) was treated with p-toluenesulfonic acid hydrate (400 mg) in toluene (40 ml) to give the target compound 8m. Yield 358 mg (27%) mp 207-209 ° C IR (KBr) cm ^-1 : 3625,3040,2960,164
0,1590,1480,1431,1305,1152 IR (CDCl ₃ ) δ: 1.47 (18H, s, 2 × Bu ^t ), 3.3
6 (2H, dt, J = 2.4, 6.4Hz, CH ₂ ), 3.84 (2H,
t, J = 6.4 Hz, CH ₂ ), 5.59 (1H, s, OH), 7.29
(2H, s, 2 × aromatic-H), 7.29-7.40 (2H, m,
CH, Py-H), 7.84-7.93 (1H, m, Py-H), 8.
37-8.64 (2H, m, 2 × Py-H) Elemental analysis _{(C 23 H 30 N 2 O} 3 S) 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

Example 14 (R ³ = 4-pyridyl) (E) -2- (4-pyridyl) -5- (3,5-di-tert-butane)
Cyl-4-hydroxy) benzylidene-1,2-isothia
Zolidine-1,1-dioxide (8n) According to the method similar to Example 1, compound 6 (2.59 gr, 9.n).
36 mmol) and N- (4-pyridyl) -1,2-isothiazolidine-1,1-dioxide 4n (2.05 gr, 10.4 mmo)
Aldol reaction with l) gave adduct 7n. Yield 2.
721 gr (61%). This adduct 7n (1.65gr, 3.46m
mol) was treated with p-toluenesulfonic acid hydrate (433 mg) in toluene (80 ml) to obtain the target compound 8n. Yield 65
8 mg (46%) mp213-214.5 ° C IR (KBr) cm ^-1 : 3400,2955,1643,159
1,1502,1437,1316,1153 NMR (CDCl ₃ ) δ: 1.47 (18H, s, 2 × Bu ^t ), 3.
37 (2H, dt, J = 2.2,6.8Hz, CH ₂ ), 3.82 (2
H, t, J = 6.8Hz, CH 2), 5.61 (1H, s, OH), 7.
21-7.25 (4H, m, 2 x aromatic-H, 2 x Py-
H), 7.42 (1H, t, J = 2.2Hz, CH), 8.50-8.
58 (2H, m, 2 × Py-H) Elemental analysis _{(C 23 H 30 N 2 O} 3 S) 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

[0066]

[Chemical 15]

Example 15 (R ³ = H) (Y = CO ₂ C (C
_{H 3) 3) (E)} -5- (3,5- di -tert- butyl-4-hydroxy
Si) benzylidene-1,2-isothiazolidine-1,1-
Dioxide (10a) In the same manner as in Example 1, compound 6a and N- (tert
-Butoxycarbonyl) -1,2-isothiazolidine-
P-Toluene was added to a toluene solution of the crude adduct 7o obtained by the aldol reaction with 1,1-dioxide 4o (prepared using 3-chloropropylsulfonyl chloride and tert-butyl carbamate as starting materials according to the method of Reaction Scheme 1). Sulfonic acid hydrate was added, and the mixture was heated under reflux for 45 minutes. Then, the reaction product was subjected to silica gel column chromatography, and the target compound 10a was obtained from the fraction eluted from the n-hexane-ethyl acetate (2: 1) mixed solution. Yield 8.5% mp23
3-234 ° C IR (CHCl ₃ ) cm ^-1 : 3618,2952,1435,13
66, 1311, 1240, 1155, 1070 NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × Bu ^t ), 3.
18 (2H, dt, J = 2.6, 6.8Hz, CH ₂ ), 3.42-
3.60 (2H, m, CH ₂ ), 4.05-4.25 (1H, broad,
NH), 5.52 (1H, s, OH), 7.22-7.27 (3H,
m, 2 × aromatic-H, CH) Elemental analysis value (C ₁₈ H ₂₇ NO ₃ S × 0.35H ₂ O) Calculated value: 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

Example 16 (R ³ = H) (Y = 4-methoxybenzyl) (Z) -5- (3,5-di-tert-butyl-4-hydroxy)
Si) benzylidene-1,2-isothiazolidine-1,1-
Dioxide (10b) Adduct 7h (1 of aldol reaction obtained by the method of Example 8
3.16gr, 25.3mmol) in toluene solution (150ml)
-Toluenesulfonic acid hydrate (1.3 gr) was added to give 30
After heating under reflux for a minute, the reaction solution was filtered through a small amount of silica gel and the solvent was distilled off under reduced pressure to obtain crude (E)-and (Z)-.
2- (4-methoxybenzyl) -5- (3,5-di-tert-
Butyl-4-hydroxy) benzylidene-1,2-isothiazolidine-1,1-dioxide mixture of 8h and 9h
(8.83 gr) was obtained. A solution of this mixture in methylene chloride (1
50 ml) and 4.1 ml of titanium tetrachloride added,
Stir for minutes. The reaction product was subjected to silica gel column chromatography, and 10a and 10b were obtained from the fraction eluted from the n-hexane-ethyl acetate (1: 1) mixed solution. Yield 1
0a: 3.35 g (41%); 10b: 120 mg (1.5%). 10
a was in agreement with the standard product obtained in Example 15. 10b: mp161
-164 ° C IR (CHCl ₃ ) cm ^-1 : 3620,2954,1432,13
71,1312,1241,1157 NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × Bu ^t ), 3.
11 (2H, dt, J = 2.1,6.7Hz, CH 2), 3.39-
3.51 (2H, m, CH ₂ ), 4.26-4.40 (1H, broad,
NH), 5.49 (1H, s, OH), 6.80 (1H, t, J = 2.
1 Hz, CH), 7.55 (2 H, s, 2 × aromatic-H). Elemental analysis value (C ₁₈ H ₂₇ NO ₃ S) Calculated value: C, 63.72; H, 8.08; N, 4 .13; S, 9.
45 Found: C, 63.64; H, 8.14; N, 4.06; S, 9.
36

Example 17 (R ³ = H) (Y = 3,4-dimethoxybenzyl) The aldol reaction adduct 7i (4.0 gr, 7.
3 mmol) of xylene solution (50 ml) was added with 2,6-di-tert-butylphenol, anisole and p-toluenesulfonic acid hydrate in equimolar amounts and heated under reflux for 45 minutes, and the reaction product was subjected to silica gel column chromatography. Attached to 1
0a and 10b were obtained. Yield 10a: 580 mg (24%); 1
0b: 85 mg (3.5%). 10a and 10b are Example 15
And the standards obtained in 16 and 16.

[0070]

[Chemical 16]

Example 18 (R ³ = CH ₂ CO ₂ C ₂ H ₅ ) (E) -2-ethoxycarbonylmethyl-5- (3,5-di)
-Tert-butyl-4-hydroxy) benzylidene-1,2
-Isothiazolidine-1,1-dioxide (8p) (E) -5- (3,5-di-tert-butyl-4-hydroxy) benzylidene-1,2-isothiazolidine-1,1-
Dioxide 10a (500 mg, 1.48 mmol), ethyl iodoacetate (240 μl, 2 mmol), 2N aqueous sodium hydroxide solution (1.5 ml, 3 mmol) and a small amount of N-benzyltrimethylammonium chloride were added to chloroform (20 ml) and water (1 ml).
0 ml) and the mixture was added sequentially and stirred at room temperature for 24 hours. The product obtained by treating the reaction solution by a conventional method was purified by silica gel column chromatography to obtain the target compound 8p. Yield 300 mg (49%) IR (CHCl ₃ ) cm ⁻¹ : 3620,2956,1747,14
35,1298,1229,1160 NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.2Hz, C
H ₃ ), 1.45 (18 H, s, 2 × Bu ^t ), 3.19 (2 H, dt,
J = 2.6,6.6Hz, CH ₂ ), 3.51 (2H, t, J = 6.6
Hz, CH ₂ ), 3.87 (2H, s, CH ₂ CO), 4.23 (2H,
q, J = 7.2 Hz, CH ₂ ), 5.52 (1 H, s, OH), 7.22
-7.30 (3H, m, 2 × aromatic-H, CH)

Example 19 (R ³ = CH ₂ COOH) (E) -2-Carboxymethyl-5- (3,5-di-tert-
Butyl-4-hydroxy) benzylidene-1,2-isothi
Azolidine-1,1-dioxide (8q) Compound 8p (610 m) obtained by a method similar to that in Example 18
g, 1.44 mmol) and 2N-sodium hydroxide aqueous solution (1.4
(5 ml) was added to a mixture of THF (10 ml) and methanol (4 ml), and the mixture was stirred at 0 ° C for 30 minutes, and then ethyl acetate was added to the reaction mixture.
(50 ml) was added, the mixture was washed with 1N-hydrochloric acid aqueous solution (20 ml) and saturated brine (20 ml), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound 8q. Yield 4
45 mg (78%), mp 175-178 ° C IR (CHCl ₃ ) cm ^-1 : 3620,2954,1735,14
35,1297,1240,1149 NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × Bu ^t ), 3.
20 (2H, dt, J = 2.6, 6.6Hz, CH ₂ ), 3.51 (2
H, t, J = 6.6Hz, CH ₂ ), 3.95 (2H, s, CH ₂ C
O), 5.54 (1H, s, OH), 7.25 (2H, s, 2 x aromat
ics-H) Elemental analysis _{(C 20 H 29 NO 5 S} ) Calculated: 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

Example 20 (R ³ = CH ₂ CH ₂ OH) (E) -2- (2-hydroxyethyl) -5- (3,5-di-
tert-butyl-4-hydroxy) benzylidene-1,2-
Isothiazolidine-1,1-dioxide (8r) compound 10a (675 mg, 2 mmol), 2-iodoethanol
(624 μl, 8 mmol), 2N-sodium hydroxide aqueous solution
(2 ml) and a small amount of N-benzyltrimethylammonium chloride were added to a mixture of methylene chloride (20 ml) and water (10 ml), and the mixture was heated under reflux for 3 days. After treating the reaction solution by a conventional method, the product was subjected to silica gel column chromatography, and the target compound 8r was obtained from the fraction eluted from the n-hexane-ethyl acetate (7: 3) mixed solution. Yield 190 mg (25
%), Mp 156-157 ° C IR (CHCl ₃ ) cm ^-1 : 3620,2950,1434,12
90 (1240), 1151, 1066. NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × Bu ^t ), 3.
16 (2H, dt, J = 2.4, 6.5Hz, CH ₂ ), 3.30 (2
H, m, CH ₂ ), 3.41 (2H, t, J = 6.5Hz, CH ₂ ), 3.
87 (2H, t, J = 5.2Hz), 5.53 (1H, s, OH), 7.
23-7.29 (3H, m, 2 × aromatic-H, CH) Elemental analysis _{(C 20 H 31 NO 4 S} ) Calculated:. 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

Example 21 (R ³ = CH ₂ CH ₂ N (CH ₃ ))
₂ ) (E) -2- (2-dimethylamino) ethyl-5- (3,5-
Di-tert-butyl-4-hydroxy) benzylidene-1,
2-Isothiazolidine-1,1-dioxide (8s) compound 10a (843 mg, 2.5 mmol), N, N-dimethyl-
2-Bromoethylamine (750 mg, 5 mmol), 2N-sodium hydroxide aqueous solution (3 ml, 6 mmol) and a small amount of N chloride.
-Benzyltrimethylammonium was added to chloroform (3
(0 ml) and water (10 ml), and the mixture was stirred under ice-cooling for 2 hours, then the chloroform layer was washed with water (20 ml × 2) and dried over anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure to obtain the target compound as a crystalline residue. Yield 950 mg (9
3%), mp 160-165 ° C IR (CHCl ₃ ) cm ^-1 : 3620,2956,1435,12
90, 1148. NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × Bu ^t ), 2.
29 (6H, s, N (CH ₃ ) ₂ ), 2.60 (2H, t, J = 6.6H
z, CH ₂ ), 3.12 (2H, dt, J = 2.2,6.6Hz, C
H ₂ ), 3.20 (2H, t, J = 6.6Hz, CH ₂ ), 3.38 (2
H, t, J = 6.6Hz, CH 2), 5.51 (1H, s, OH), 7.
21-7.28 (3H, m, 2 × aromatic-H, CH) Elemental analysis _{(C 22 H 36 N 2 O} 3 S × 0.2CH 2 Cl 2) Calculated:. 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

Example 22 (R ³ = COCH ₃ ) (E) -2-acetyl-5- (3,5-di-tert-butyl-
4-hydroxy) benzylidene-1,2-isothiazolidi
1,1-dioxide (8t) compound 10a (585 mg, 1.74 mmol) in pyridine (1
(0 ml), a small amount of 4-N, N-dimethylaminopyridine was added, and 6 ml of acetic anhydride was added dropwise under ice cooling, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and filtered through a small amount of silica gel, and the solvent was concentrated under reduced pressure to obtain the target compound as a crystalline residue.
Yield 360 mg (55%), mp 177-179 ° C IR (CHCl ₃ ) cm ^-1 : 3618,2958,1695,14
35, 1379, 1297, 1153, 1117 NMR (CDCl ₃ ) δ: 1.46 (18H, s, 2 × Bu ^t ), 2.
53 (3H, s, COCH ₃ ), 3.20 (2H, dt, J = 2.2,
_{7.0Hz, CH 2), 3.86 (} 2H, t, J = 7.0Hz, C
H ₂ ), 5.60 (1H, s, OH), 7.52 (2H, s, 2 × aroma
. tic-H), 7.39 ( 1H, t, J = 2.2Hz, CH) Elemental analysis _{(C 20 H 29 NO 4 S} ) Calculated: 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

Example 23 (R ³ = N-methyl-N-methoxy) (E) -2- (N-methyl-N-methoxy) carbamoyl-
5- (3,5-di-tert-butyl-4-hydroxy) ben
Dilidene-1,2-isothiazolidine-1,1-dioxy
De (8u) compound 10a (450 mg, 1.33 mmol) and N-methyl-
N-methoxy-O-phenyl carbamate (300 mg,
1.66 mmol) was dissolved in a mixed solution of THF (10 ml) and HMPA (10 ml), and cooled to −40 ° C. under stirring with lithium hexamethyldisilazane (LiHMDS) in THF (1M, 3.
(2 ml) was added dropwise, and the reaction solution was warmed to room temperature. The reaction solution was poured into a 1N hydrochloric acid aqueous solution (20 ml) and ethyl acetate (3
The mixture was extracted with 0 ml), the ethyl acetate layer was washed with water (30 ml) and saturated saline (30 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, and the target compound 8u was obtained from the fraction eluted with a mixed liquid of n-hexane-ethyl acetate (7: 3). Yield 23
0 mg (41%) IR (CHCl ₃ ) cm ⁻¹ : 3620,2958,1673,14
35, 1388, 1330, 1240, 1207, 1155,
1092. NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × Bu ^t ), 3.
21 (2H, dt, J = 2.2,6.8Hz, CH ₂ ), 3.31 (3
H, s, NCH ₃ ), 3.78 (3H, s, OCH ₃ ), 3.89 (2
H, t, J = 6.8Hz), 5.54 (1H, s, OH), 7.23 (2)
H, s, 2 × aromatic-H), 7.31 (1H, t, J = 2.2H
z, CH)

Example 24 (R ³ = N-benzyloxy-N-methoxymethyl) (E) -2- (N-benzyloxy-N-methoxymethyl)
Carbamoyl-5- (3,5-di-tert-butyl-4-hi)
Droxy) benzylidene-1,2-isothiazolidine-
The 1,1-dioxide (8v) compound 10a (424 mg, 1.26 mmol) and N-benzyloxy-N-methoxymethyl-O-phenylcarbamate (722 mg, 2.52 mmol) were treated with THF in the same manner as in Example 23. (90 ml) and HMPA (30 ml) in a mixed solution
The reaction product was treated with a THF solution of iHMDS (1M, 4.0 ml), and the reaction product was subjected to silica gel chromatography and eluted with a n-hexane-ethyl acetate (3: 1) mixture to obtain the target compound 8v. . Yield 600 mg (90%) NMR (CDCl ₃ ) δ: 1.45 (18 H, s, 2 × Bu ^t ), 3.
18 (2H, dt, J = 2.0, 6.8Hz, CH ₂ ), 3.45 (3
H, s, OCH ₃ ), 3.79 (2H, t, J = 6.8Hz, CH ₂ ),
4.94 (2H, s, OCH ₂ ), 5.02 (2H, s, OCH ₂ ),
5.54 (1H, s, OH), 7.22 (2H, s, 2 × aromatic-
H), 7.30 (1H, t, J = 2.0Hz, CH), 7.30-7.
55 (5H, m, 5 × aromatic-H).

Example 25 (R ³ = CONHOH) (E) -2- (hydroxycarbamoyl) -5- (3,5-di)
-Tert-butyl-4-hydroxy) benzylidene-1,2
-Isothiazolidine-1,1-dioxide (8w) In a methylene chloride solution (8 ml) of the compound 8v (600 mg, 1.13 mmol) obtained in Example 24 under ice cooling, titanium tetrachloride (5
(00 μl, 4.56 mmol) was added and the mixture was stirred for 1.5 hours. To the reaction solution was added 2N-hydrochloric acid aqueous solution (10 ml) and the mixture was stirred at room temperature for 30 minutes, the reaction solution was extracted with methylene chloride (20 ml), the organic layer was washed with saturated brine (20 ml) and dried over anhydrous sodium sulfate. did. The solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, and the target compound 8w was obtained from the fraction eluted with a n-hexane-ethyl acetate (1: 1) mixed solution. Yield 150 mg (33%) IR (CHCl ₃ ) cm ⁻¹ : 3618,2956,1707,14
34, 1320, 1151, 1100. NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × Bu ^t ), 3.
23 (2H, dt, J = 2.2, 7.0Hz, CH ₂ ), 3.94 (2
H, t, J = 7.0Hz, CH 2), 5.61 (1H, s, OH), 6.
85-6.95 (1H, broad, OH), 7.24 (2H, s, 2x
aromatic-H), 7.30 (1H, t, J = 2.2Hz, CH),
8.61 (1H, s, NH).

[0079]

[Chemical 17]

Example 26 (E) -2-Hydroxy-5- (3,5-di-tert-butyl)
Lu-4-hydroxy) benzylidene-1,2-isothiazo
Lysine-1,1-dioxide (11a) and its (Z) -isomerism
Form (11b) The aldol reaction of compound 6a with N-benzyloxy-1,2-isothiazolidine-1,1-dioxide was carried out in the same manner as in Example 1, and then the aldol reaction adduct was treated with p-toluenesulfonic acid. Crude 2-benzyloxy-5- (3,5-di-tert-butyl-4-hydroxy) benzylidene-1,2-isothiazolidine-1,1-dioxide (4. 44 g, 10 mmol) in methylene chloride solution (80 ml) with stirring under ice cooling and titanium tetrachloride.
(4.4 ml, 40 mmol) was added dropwise, and stirring was continued at the same temperature for 2 hours. A 1N-hydrochloric acid aqueous solution (50 ml) was added to the reaction solution, the methylene chloride layer was separated, and water (50 ml) and saturated saline (5 ml) were added.
It was washed successively with 0 ml) and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and target compounds 11b and 11a were sequentially obtained from the fractions eluted with n-hexane-ethyl acetate (3: 1) mixed solution.

Yield 11a: 1.6 gr (45%); 11b: 178
mg (5%) 11a: mp 177-182 ° C. (d) IR (KBr) cm ⁻¹ : 3560,3430,1425,133
0,1240,1155,1130,1115 NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × Bu ^t ), 3.
18 (2H, dt, J = 2.6, 6.8Hz, CH ₂ ), 3.89 (2
H, t, J = 6.8Hz, CH 2), 5.56 (1H, s, OH), 6.
18-6.30 (1H, broad, OH), 7.26-7.35 (3
H, m, 2 × aromatic-H, CH) Elemental analysis value (C ₁₈ H ₂₇ NO ₄ S) Calculated value: 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 11b: mp 190-198 ° C. (d) IR (CHCl ₃ ) cm ⁻¹ : 3622,3540,3020,29
54,1632,1431,1340,1241,1157 NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × Bu ^t ), 3.
17 (2H, dt, J = 2.2, 6.8Hz, CH ₂ ), 3.62 (2
H, m, CH ₂ ), 5.51 (1H, s, OH), 6.22 (1H, s, O)
H) 7.04 (1H, t, J = 2.2Hz, CH), 7.49 (2H,
s, 2 × aromatic-H) Elemental analysis value (C ₁₈ H ₂₇ NO ₄ S) Calculated value: C, 60.16; H, 7.70; N, 3.96; S, 9.
07 Found: C, 60.67; H, 7.58; N, 3.96; S, 8.
87

Example 27 (E) -2-Isopropyl-5- (3,5-di-tert-butane
Cyl-4-hydroxy) benzylidene-1,2-isothi
Azolidine-1,1-dioxide (8x)

[Chemical 18] According to the method of Example 1, N-isopropyl-1,2-
Isothiazolidine-1,1-dioxide 4p (3.
65 gr, 22.4 mmol) and 3,5-di-tert-butyl-4-methoxymethoxybenzaldehyde (6a)
The adduct (7p) was obtained as a white powder by aldol reaction with (5.28 gr, 19.0 mmol). Yield 6.27
gr (74.7%). This aldol adduct 7p (6.2
7 gr) was dissolved in toluene (120 ml), p-toluenesulfonic acid hydrate (600 mg) was added, the mixture was heated under reflux for 30 minutes, the reaction solution was cooled, and then washed twice with water (100 ml), Dry over anhydrous sodium sulfate and remove the solvent under reduced pressure. The crystalline residue was recrystallized from methanol to obtain the target compound as colorless columnar crystals. Yield 2.16 gr (30
%). 8x: mp 148-150 degreeC IR (KBr) cm < ^-1 >: 3550,2960,164.
5,1600,1432,1273,1173 NMR (CDCl ₃ ) δ: 1.29 (6H, d, J =
_{6.6Hz, 2 × CH 3),} 1.45 (18H, s, 2
^{× Bu t), 3.07~3.14 (2H} , m, C
H ₂ ), 3.29 to 3.35 (2H, m, CH ₂ ),
3.94 (1H, sept, CH), 5.48 (1H,
s, OH), 7.22 (1H, t, J = 2.8Hz, C
H), 7.23 (2H, s , Ar-H) Elemental analysis _{(C 21 H 33 NO 3 S} ) Calcd: C, 66.45; H, 8.76 ; N, 3.6
9; S, 8.45 Found: C, 66.37; H, 9.01; N, 3.6.
7; S, 8.28

Example 28 (E) -2-Ethyl-5- (3,5-dimethyl-4-high
Droxy) benzylidene-1,2-isothiazolidine-
1,1-dioxide (8y)

[Chemical 19] According to the method of Example 1, N-ethyl-1,2-isothiazolidine-1,1-dioxide 4a (2.5 gr, 1
6.8 mmoml) and 3,5-dimethyl-4-methoxymethoxybenzaldehyde (6b) (2.92 gr, 15 mm
Aldol reaction with ol) gave adduct (7q) as a white powder. Yield 4.01 gr (77.8%). This aldol adduct 7q (3.75 gr, 10.9 mmol) was dissolved in toluene (100 ml), p-toluenesulfonic acid hydrate (200 mg) was added, and the mixture was heated under reflux for 30 minutes and the reaction solution was cooled. After that, wash twice with water (100 ml),
Dry over anhydrous sodium sulfate and remove the solvent under reduced pressure. The crystalline residue was recrystallized from methanol to obtain the target compound as colorless columnar crystals. Yield 1.63 gr (53%). 8y: mp167-168 degreeC IR (Nujol) cm < ^-1 >: 3399,1641,159.
3,1489,1461,1272,1217,117
0, 1145, 1128 NMR (CDCl ₃ ) δ: 1.29 (3H, t, J =
_{7.4Hz, CH 3), 2.26 (} 6H, s, 2 × CH
_{3), 3.05~3.36 (6H, m} , 2 × CH 2, N
CH ₂ ), 5.00 (1H, broad, OH), 7.
04 (2H, s, Ar-H), 7.15 (1H, t, J
= 2.8 Hz, CH) Elemental analysis value (C ₁₄ H ₁₉ NO ₃ S) Calculated value: C, 59.76; H, 6.81; N, 4.9
8; S, 11.39 Found: C, 59.56; H, 6.85; N, 4.9.
9; S, 11.38

Example 29 (E) -2-Ethyl-5- (3,5-diisopropyl-4)
-Hydroxy) benzylidene-1,2-isothiazoli
Gin-1,1-dioxide (8z)

[Chemical 20] Using a method similar to Example 1, N-ethyl-1,2-isothiazolidine-1,1-dioxide 4a (4.9 g
r, 32.8 mmol) and 3,5-diisopropyl-4-methoxymethoxybenzaldehyde (6c) (7.51 g)
r, 30 mmol) and the adduct (7
r) was obtained as a white powder. Yield 6.07gr (50.6
%). This aldol adduct 7r (5.0 gr, 20 mmol)
Was dissolved in toluene (100 ml), p-toluenesulfonic acid hydrate (200 mg) was added, and the mixture was heated under reflux for 30 minutes. After cooling the reaction solution, it was washed twice with water (100 ml) and dried. Dry with sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crystalline residue, which was recrystallized from methanol to obtain the target compound 8z as colorless columnar crystals. Yield 3.24 gr
(48%). 8z: mp167-168 ° C. IR (Nujol) cm ⁻¹ : 3413, 1644, 160
0,1472,1276,1194,1153,111
5 NMR (CDCl ₃ ) δ: 1.27 (12H, d, J =
6.6 Hz, 2 × CH (CH 3) 2), 3.06 ~ 3.3
6 (8H, m, 3 × CH ₂ , 2 × CH), 5.13 (1
H, s, CH), 7.12 (2H, s, Ar-H), 7.24
(1H, t, J = 2.8 Hz, CH) Elemental analysis value (C ₁₈ H ₂₇ NO ₃ S) Calculated value: C, 64.06; H, 8.07; N, 4.1
5; S, 9.50 Found: C, 64.03; H, 8.02; N, 4.1.
1; S, 9.46

Example 30 (E) -2-Ethyl-5- (3,5-dimethoxy-4-ha)
Idoxy) benzylidene-1,2-isothiazolidine
-1,1-dioxide (8Ia)

[Chemical 21] N-Ethyl-1,2-isothiazolidine-1,1-dioxide 4a (5.22 g) was prepared in the same manner as in Example 1.
r, 35 mmol) and 3,5-dimethoxy-4-methoxymethoxybenzaldehyde (6d) (6.77 gr, 3
Aldol reaction with 0 mmol) gave the adduct 7s as a white powder. Yield 8.42 gr (74.8%). This aldol adduct 7s (4.28 gr, 11.4 mmol) was dissolved in toluene (100 ml), p-toluenesulfonic acid hydrate (200 mg) was added, and the mixture was heated under reflux for 30 minutes to give a reaction solution. After cooling, it is washed twice with water (100 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crystalline residue was recrystallized from methanol to obtain the target compound 8Ia as colorless needle crystals. Yield 1.64 gr (4
6%). 8Ia: mp164-166 ° C IR (Nujol) cm ^-1 : 3434,1643,160
7,1593,1517,1454,1321,127
3,1251,1219,1172,1149,110
9 NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.4)
_{Hz, CH 3), 3.10~3.37 (} 6H, m, 3 ×
CH ₂ ), 3.92 (6H, s, 2 x OCH ₃ ), 5.76
(1H, s, OH), 6.65 (2H, s, Ar-H),
7.20 (1 H, t, J = 2.8 Hz, CH) Elemental analysis value (C ₁₄ H ₁₉ NO ₅ S) Calculated value: C, 53.66; H, 6.11; N, 4.4
7; S, 10.23 Found: C, 53.45; H, 6.06; N, 4.4.
4; S, 10.33

Example 31 (E) -2-Ethyl-5- (3-methoxy-4-hydro
Xy) benzylidene-1,2-isothiazolidine-1,1
-Dioxide (8Ib)

[Chemical formula 22] By a method similar to that in Example 1, N-ethyl-1,2-isothiazolidine-1,1-dioxide 4a (5.00 g
r, 33.5 mmol) and 3-methoxy-4-methoxymethoxybenzaldehyde (6e) (5.88 gr, 30 m)
Aldol reaction with (mol) gave adduct 7t as a white powder. Yield 4.35 gr (42%). This aldol adduct 7t (4.30 gr, 12.4 mmol) was dissolved in toluene (100 ml), p-toluenesulfonic acid hydrate (200 mg) was added, and the mixture was heated under reflux for 30 minutes.
The reaction mixture is washed twice with water (200 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with n-hexane: ethyl acetate (2: 1) was isolated and recrystallized from a mixed solution of methylene chloride and diisopropyl ether to give the desired compound as colorless columnar crystals. Obtained. Yield 2.7 gr (31.
8%). 8Ib: mp146-148 ° C IR (Nujol) cm ^-1 : 3404, 2924,164
6,1611,1594,1516,1462,127
0,1149,1130 NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.4)
Hz, CH ₃ ), 3.08 to 3.18 (2H, m, C
H ₂ ), 3.17 (2H, q, J = 7.4 Hz, 2 × CH
_{2), 3.26 ~ 3.34 (2H} , m, CH 2), 3.92
(3H, s, OCH ₃ ) 5.88 (1H, s, OH), 6.
86 to 7.02 (3H, m, Ar-H), 7.21 (1
H, t, J = 2.8 Hz, CH) Elemental analysis value (C ₁₃ H ₁₇ NO ₄ S) Calculated value: C, 55.11; H, 6.05; N, 4.9
4; S, 11.32 Found: C, 54.75; H, 6.11; N, 4.9.
9; S, 11.23

Example 32 (E) -2-Ethyl-5- (4-hydroxy) benzilide
1,2-isothiazolidine-1,1-dioxide
(8Ic)

[Chemical formula 23] N-Ethyl-1,2-isothiazolidine-1,1-dioxide 4a (3.28) was prepared in the same manner as in Example 1.
Gr, 22 mmol) and 4-methoxymethoxybenzaldehyde (6f) (3.32 gr, 20 mmol) were subjected to aldol reaction to obtain adduct 7u as a white powder. Yield 4.10 gr (65%). This aldol adduct 7u (4.
(00 gr, 12.7 mmol) was dissolved in toluene (100 ml), and p-toluenesulfonic acid hydrate (200 mg) was dissolved.
Was added and the mixture was heated under reflux for 30 minutes, and then the reaction solution was mixed with water (200
(ml), washed twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with n-hexane: ethyl acetate (3: 2) was isolated. Methylene chloride: diisopropyl ether
Recrystallization from a tellurium mixture gave the target compound as colorless columnar crystals. Yield 1.0 gr (31.1%) 8Ic: mp135-138 ° C IR (Nujol) cm ^-1 : 3346, 2914,164
6,1605,1584,1513,1453,137
6,1282, 1223, 1136 NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.2)
Hz, CH ₃ ), 3.04 to 3.12 (2H, m, C
H ₂ ), 3.17 (2H, q, J = 7.2 Hz, CH ₂ ),
3.27 ~ 3.33 (2H, m, CH 2), 5.59 (1
H, s, OH), 6.85 to 6.90 (2H, m, Ar-
H), 7.19 (1H, t, J = 2.8 Hz, CH), 7.
24 ~ 7.30 (4H, m, Ar-H) Elemental analysis _{(C 12 H 15 NO 3 S} ) Calcd: C, 56.90; H, 5.97 ; N, 5.5
3; S, 12.66 Found: C, 56.74; H, 5.98; N, 5.5.
2; S, 12.41

Example 33 (E) -2- (3,5-di-tert-butyl-4-hydroxy)
Si) benzylidene sulfolane (8Id)

[Chemical formula 24] In the same manner as in Example 1, sulfolane 4q (2.4
gr, 20 mmol) and 3,5-di-tert-butyl-4-
Methoxymethoxybenzaldehyde 6a (5.57 gr,
Aldol reaction with 20 mmol) gave adduct 7v as a white powder. Yield 5.58 gr (70%). This aldol adduct 7v (4.0 gr, 10.0 mmol) was dissolved in toluene (100 ml), p-toluenesulfonic acid hydrate (200 mg) was added, and the mixture was heated under reflux for 30 minutes, and then the reaction solution was mixed with water. Wash twice with (200 ml), dry over anhydrous sodium sulfate, concentrate the solvent under reduced pressure, subject the residue to silica gel column chromatography, and elute with n-hexane: ethyl acetate (3: 1). Collect, concentrate under reduced pressure, n-
Recrystallization from a hexane: ether mixed liquid gave the target compound as colorless columnar crystals. Yield 1.346 gr (40%). 8Id: mp152-154 degreeC IR (Nujol) cm < ^-1 >: 3608,2914,163.
8, 1597, 1461, 1376, 1285, 121
4,1133 NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × Bu
^t ), 2.31 (2H, q, J = 7 Hz, CH ₂ ), 3.0
0 ~ 3.07 (4H, m, 2 × CH 2), 5.51 (1
H, s, OH), 7.22 (1H, t, J = 2.6Hz, C
H), 7.26 (2H, s , Ar-H) Elemental analysis _{(C 19 H 28 O 3 S} ) Calcd: C, 67.82; H, 8.38 ; S, 9.53 Found: C, 67.90; H, 8.38; S, 9.34.

Example 34 (E) -6- (3,5-di-tert-butyl-4-hydro
Xy) benzylidene-2-methyl-4,5-dihydro-
6H-1,3,2-thiaoxazine-1,1-dioxa
Id (8Ie)

[Chemical 25] By the same method as in Example 1, N-methyl-1,3,2-
Thiaoxazine-1,1-dioxide 4r (575
mg, 3.80 mmol) and 3,5-di-tert-butyl-4-methoxymethoxybenzaldehyde 6a (84
The adduct 7w was obtained as a white powder by an aldol reaction with 6 mg, 3.04 mmol). Yield 1.458 gr. This aldol adduct 7w (1.458 gr) was added to toluene (50
ml), p-toluenesulfonic acid hydrate (1
(50 mg) and heated under reflux for 30 minutes, the reaction product was subjected to silica gel column chromatography, and the target compound was obtained as colorless crystals from the fraction eluted with a n-hexane: ethyl acetate (6: 1) mixture. Obtained. Yield 511 mg (4
3%). 8Ie: mp215-216.5 ° C. IR (KBr) cm ⁻¹ : 3599,3438,296.
0,1637,1599,1437,1326,129
8,1153 NMR (CDCl ₃ ) δ: 1.44 (18H, s, 2 ×)
^{Bu t), 3.00 (3H,} s, CH 3), 3.26 ~ 3.
32 (2H, m, CH ₂ ), 4.12 to 4.17 (2H,
m, CH ₂ ), 5.49 (1H, s, OH), 7.15 (2
H, s, Ar-H), 7.55 (1H, broad, CH) Elemental analysis value (C ₁₉ H ₂₉ NO ₄ S) Calculated value: C, 62.10; H, 7.95; N, 3. 8
1; S, 8.72 Found: C, 62.03; H, 7.91; N, 3.9.
2; S, 8.51

Example 35 (E) -6- (3,5-di-tert-butyl-4-hydro)
Xy) benzylidene-2-methoxy-3,4,5,6-
Tetrahydro-1,2-thiazin-1,1-dioki
Side (8If)

[Chemical formula 26] In the same manner as in Example 1, N-methoxy-3,4,4
5,6-Tetrahydro-1,2-thiazin-1,1
The adduct 7x by aldol reaction with -dioxide 4s (2.73 gr, 16.5 mmol) and 3,5-di-tert-butyl-4-methoxymethoxybenzaldehyde 6a (5.0 gr, 18 mmol). Obtained. Yield 7.3 gr. P-Toluenesulfonic acid hydrate (200 mg) was added to a toluene solution (100 ml) of the present aldol adduct 7x (2.1 gr, 4.73 mmol), and the mixture was heated under reflux for 30 minutes. Subject to column chromatography,
The target compound was obtained as a brown powder from the fraction eluted with a mixed solution of n-hexane: ethyl acetate (4: 1). Yield 750 m
g (42%). IR (CHCl ₃ ) cm ⁻¹ : 3618, 2950, 163
0,1435,1340,1238,1161 NMR (CDCl ₃ ) δ: 1.45 (18H, s, 2 × B)
u ^t ), 1.80 to 1.95 (2H, m, CH ₂ ), 3.0
4 (2H, t, J = 6.0, Hz, CH 2), 3.77 ~
3.83 (2H, m, CH ₂ ), 3.80 (3H, s, OC
H ₃ ), 5.46 (1H, s, OH), 7.20 (2H, s,
Ar-H), 7.46 (1H, s, CH)

Example 36 (E) -5- (3,5-di-tert-butyl-4-hydro)
Xy) benzylidene-2-ethyl-1,2-isothiazo
Lysine-3-one-1,1-dioxide (8Ig) (1) (3,5-di-tert-butyl-4-methoxymethoate
Xybenzoyl) -N-ethyl-N-diphenylmethyl
Methane sulfonamide (14)

[Chemical 27]

N-Ethyl-N-diphenylmethylmethanesulfonamide ( 12 ) was prepared by reacting methanesulfonyl chloride with diphenylmethylamine in the presence of triethylamine by a conventional method, followed by addition of ethyl iodide in the presence of potassium carbonate. It was synthesized by acting.
3,5-di-tert-butyl-4-methoxymethoxy-N
-Methyl-N-methoxybenzamide ( 13 ) is 3,5
It was synthesized by converting -di-tert-butyl-4-hydroxybenzoic acid into an acid chloride by a conventional method, reacting it with N, O-dimethylhydroxylamine, and methoxymethylating the phenolic hydroxyl group. The compound ( 12 ) (1
A THF solution (200 ml) of 6.82 g, 58 mmol) was added to -5
After cooling to below 0 ° C., a solution of lithium bistrimethylsilylamide in THF (1.0 M) (64 ml, 64 mmol) is slowly added dropwise, and the mixture is stirred at −50 ° C. for 30 minutes. Next compound
THF solution (100 m) of ( 13 ) (17.7 g, 52.2 mmol)
l) was slowly added dropwise under the same conditions, and the mixture was washed with THF (30 ml), the reaction system was warmed to room temperature, saturated aqueous ammonium chloride solution (500 ml) was added, and the mixture was extracted with ethyl acetate (400 ml). To do. The separated organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (500 ml) and saturated brine (500 ml), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (9: 1 to 7: 1) for purification,
14 was obtained as a colorless oil. Yield 27.2 g (92%) IR (CHCl ₃ ) cm ^-1 : 2960,1673,1339,11
88 NMR (CDCl ₃ ) δ: 0.83 (3H, t, J = 7.0Hz,
CH ₃ ), 1.45 (18H, s, 2 × ^t Bu), 3.56 (2H,
q, J = 7.0 Hz, CH ₂ ), 3.65 (3H, s, CH ₃ ), 4.
37 (2H, s, CH ₂ ), 6.42 (1H, s, CH), 7.31
~ 7.38 (10H, m, 10 x aromatic-H), 7.89
(2H, s, 2 × aromatic-H)

(2) tert-Butyl 3- (3,5-di-
tert-butyl-4-methoxymethoxybenzoyl) -3
-(N-ethyl-N-diphenylmethylsulfamoyl)
Propionate (15)

[Chemical 28] (3,5-di-tert-butyl-4-methoxymethoxybenzoyl) -N-ethyl-N-diphenylmethylmethanesulfonamide ( 14 ) (27.0 g, 47.7 mmol), tert
-Butyl bromoacetate (9.25 ml, 57.3 mmol)
And potassium carbonate (9.89 g, 71.6 mmol) in DM
The F (300 ml) suspension was stirred for 18 hours at room temperature, 600 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (800 ml).
The organic layer was separated, water (300 ml), saturated saline (500 ml)
It was washed with and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a pale yellow solid. This was washed well with n-hexane and concentrated under reduced pressure to give 15 as a colorless powder. Yield 26.75 g (82%). mp. 104 ~
105 ° C IR (KBr) cm ^-1 : 3435,1735,1677,134
0,1164,1147 NMR (CDCl ₃ ) δ: 0.77 (3H, t, J = 7.0Hz,
CH ₃ ), 1.21 (9H, s, ^t Bu), 1.44 (18H, s, 2
× ^t Bu), 2.83 (1H, dd, J = 3.2,16.8Hz, C
H ₂ × 1/2), 3.29 to 3.51 (3H, m, CH ₂ + CH
_{2 × 1/2), 3.65} (3H, s, CH 3), 4.90 (2H, s,
CH ₂ ), 5.28 (1H, dd, J = 3.2, 10.4Hz, C
H), 6.39 (1H, s, CH), 7.31 to 7.34 (10
H, m, 10 × aromatic-H), 7.96 (2H, s, 2 × aroma
tic-H) Elemental analysis value (C ₃₉ H ₅₃ NO ₇ S) Calculated value C, 68.90; H, 7.86; N, 2.06; S,
4.72 Found C, 68.80; H, 7.93; N, 2.16; S,
4.55

(3) tert-Butyl 4- (3,5-di-
tert-butyl-4-methoxymethoxyphenyl) -4-
Hydroxy-3- (N-ethyl-N-diphenylmethyl
Sulfamoyl) butyrate (16)

[Chemical 29] tert-butyl 3- (3,5-di-tert-butyl-4
-Methoxymethoxybenzoyl) -3- (N-ethyl-N
-Diphenylmethylsulfamoyl) propionate ( 1
5 ) (22.6 g, 33.2 mmol) in MeOH (180 ml) and CH ₂ Cl ₂ (180 ml) was added sodium borohydride (1.89 g, 49.9 mmol) little by little under ice cooling. After warming to room temperature, stir for 45 minutes. Add 5 ml of acetone to the reaction solution, and add 4 parts of saturated aqueous ammonium chloride solution.
Add 00 ml and extract with methylene chloride (400 ml). The organic layer was separated, washed with water (400 ml) and saturated brine (400 ml), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a pale pink solid, which was well washed with n-hexane to obtain 16 as a colorless powder. Yield 21.
8g (96%) IR (KBr) cm ^-1 : 3499,2970,1737,160
0,1319,1151 NMR (CDCl ₃ ) δ: 0.84 (3H, t, J = 7.0Hz,
CH ₃ ), 1.21 (9H, s, ^t Bu), 1.41 (18H, s, 2
× ^t Bu), 2.22 (1H, dd, J = 6.6, 17.6Hz, C
H ₂ × 1/2), 2.48 (1H, dd, J = 4.2,17.6)
Hz, CH ₂ × 1/2), 3.37 to 3.58 (2H, m, C
H ₂ ), 3.62 (3H, s, CH ₃ ), 3.92 to 4.07 (1
H, m, CH), 4.14 (1H, d, J = 2.2Hz, OH),
_{4.86 (2H, s, CH 2} ), 4.97 (1H, dd, J = 2.
2,9.2Hz, CH), 6.47 (1H, s, CH), 7.19
(2H, s, 2 × aromatic-H), 7.32 to 7.34 (10
H, m, 10 × aromatic-H) Elemental analysis value (C ₃₉ H ₅₅ NO ₇ S.0.7H ₂ O) Calculated value C, 67.44; H, 8.18; N, 2.02; S,
4.62 found C, 67.50; H, 8.06; N, 2.15; S,
4.51

(4) tert-butyl 4- (3,5-di-te)
rt-Butyl-4-methoxymethoxyphenyl) -4-hi
Droxy-3- (N-ethylsulfamoyl) butyrate
(17)

[Chemical 30] tert-Butyl 4- (3,5-di-tert-butyl-4-methoxymethoxyphenyl) -4-hydroxy-3- (N-
Ethyl-N-diphenylmethylsulfamoyl) butyrate ( 16 ) (20.8 g, 30.5 mmol) and palladium hydroxide-carbon (3.05 g) in THF (100 ml) in methanol (200 ml) was added with hydrogen. Stir at room temperature under an atmosphere for 5 hours. The catalyst was removed by filtration through Celite, the filtrate was concentrated,
The residue was recrystallized from ether-n-hexane to obtain 17 . Yield 13.69 g (87%) mp. 96-
97 ° C IR (KBr) cm ^-1 : 3441, 3298, 2966, 173
6,1635,1367,1152 NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.4Hz,
CH ₃ ), 1.36 (9H, s, ^t Bu), 1.44 (18H, s, 2
× ^t Bu), 2.31 (1H, dd, J = 5.6, 17.6Hz, C
H ₂ × 1/2), 2.80 (1H, dd, J = 6.6,17.6)
Hz, CH ₂ × 1/2), 3.00 to 3.27 (2H, m, C
H ₂ ), 3.40 (1H, d, J = 4.8Hz, OH), 3.64
(3H, s, CH ₃ ), 3.97 (1H, ddd, J = 5.6,6.
6,8.2 Hz, CH), 4.19 to 4.25 (1 H, m, N
H), 4.89 (2H, s, CH ₂ ), 4.95 (1H, dd, J =
4.8, 8.2Hz, CH), 7.27 (2H, s, 2 x aromati
c-H) Elemental analysis _{(C 26 H 45 NO 7 S} ) Calcd C, 60.56; H, 8.80; N, 2.72; S,
6.22 observed C, 60.37; H, 8.72; N, 2.69; S,
6.17

(5) 5- (3,5-di-tert-butyl-
4-hydroxyphenyl) -4- (N-ethylsulfamo)
Yl) -γ-butyrolactone (18)

[Chemical 31] tert-Butyl 4- (3,5-di-tert-butyl-4-methoxymethoxyphenyl) -4-hydroxy-3- (N-
Ethylsulfamoyl) butyrate ( 17 ) (1.10 g,
2.13 mmol of chloroform solution (30 ml) was added to iodotrimethylsilane (TMSI) (0.91 ml, under ice cooling).
6.39 mmol) is added all at once, and the mixture is stirred at the same temperature for 30 minutes.
A 5% aqueous sodium thiosulfate solution (70 ml) was added to the reaction solution, and the mixture was extracted twice with methylene chloride (60 ml). The combined organic layers were washed twice with saturated brine (70 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (3: 1) for purification to obtain 18 as a colorless solid. Yield 481 mg (57%) mp. 129-131 ° C IR (CHCl ₃ ) cm ^-1 : 3626,3374,3288,29
60, 1785, 1436, 1331 NMR (CDCl ₃ ) δ: 1.08 (3H, t, J = 7.2Hz,
_{CH 3), 1.44 (18H,} s, 2 × t Bu), 2.90~3.
22 (2H, m, CH ₂ ), 3.07 (2H, d, J = 7.6Hz,
CH ₂ ), 3.94 (1H, dt, J = 5.0,7.6Hz, C
H), 4.25 (1H, broad t, J = 6.0Hz, NH), 5.
38 (1H, s, OH), 5.72 (1H, d, J = 5.0Hz, C
H), 7.12 (2H, s, 2 × aromatic-H) Elemental analysis value (C ₂₀ H ₃₁ NO ₅ S) Calculated value C, 60.43; H, 7.86; N, 3.52; S ,
8.07 found C, 60.32; H, 7.84; N, 3.55; S,
7.85

(6) (E) -4- (3,5-di-tert-butane)
Cyl-4-hydroxyphenyl) -3- (N-ethylsulfur)
Famoyl) -3-butenoic acid (19)

[Chemical 32] 5- (3,5-di-tert-4-hydroxyphenyl) -4
-(N-ethylsulfamoyl) -γ-butyrolactone
( 18 ) (1.516 g, 3.81 mmol) in benzene (5
DBU (1.14 mmol, 7.62 mmol) was added to 0 ml) and the mixture was stirred for 30 minutes under the same conditions. 1N-HCl (60 m
l) is added and extracted with ethyl acetate (70 ml). The organic layer was separated, washed with water (60 ml) and saturated brine (60 ml), and dried over anhydrous sodium sulfate. When the solvent was distilled off under reduced pressure, 1
9 was obtained as a colorless solid. Yield 1.52 g (quant) mp. 169-172 ° C IR (KBr) cm ^-1 : 3604,3267,2958,171
9,1631, 1596, 1430, 1326, 1158 NMR (CD ₃ OD) δ: 1.15 (3H, t, J = 7.4Hz,
CH ₃ ), 1.43 (18H, s, 2 × ^t Bu), 2.99 (2H,
q, J = 7.4 Hz, CH ₂ ), 3.63 (2H, s, CH ₂ ), 7.
29 (2H, s, 2 × aromatic-H), 7.58 (1H, s, C
H) Elemental analysis value (C ₂₀ H ₃₁ NO ₅ S) Calculated value C, 60.43; H, 7.86; N, 3.52; S,
8.07 found C, 60.36; H, 7.95; N, 3.54; S,
7.87

(7) (E) -5- (3,5-di-tert-
Butyl-4-hydroxy) benzylidene-2-ethyl
-1,2-isothiazolidin-3-one-1,1-dio
Kide (8Ig)

[Chemical 33] (E) -N-Ethylaminosulfonyl-4- (3,5-di-tert-butyl-4-hydroxy) phenyl-3-butenoic acid 19 (1.52 gr, 3.81 mmol) and triethylamine (0.737 ml). , 1.5 eq) in methylene chloride solution (60 ml), ethyl chlorocarbonate (0.437 ml, 1.2 eq) was added dropwise with stirring while cooling with ice water.
Stir for 0 minutes. Water (60 ml) was added to the reaction mixture, extraction was performed with methylene chloride (50 ml), the organic layer was washed with saturated brine (70 ml), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the crude crystals obtained were washed with ether to obtain the target compound as colorless columnar crystals. yield
1.30 gr (89.9%). 8Ig: mp188-190 degreeC IR (KBr) cm < ^-1 >: 3559,2960,171.
5,1641, 1598, 1434, 1317, 115
9 NMR (CDCl ₃ ) δ: 1.38 (3H, t, CH ₃ ),
1.46 (18H, s, 2 × Bu t), 3.74 (2H,
q, J = 7.2 Hz, CH ₂ ), 3.80 (2H, d, J =
2.4 Hz, CH ₂ ), 5.64 (1 H, s, OH), 7.
23 (2H, s, Ar-H), 7.45 (1H, t, J =
2.4 Hz, CH) Elemental analysis value (C ₂₀ H ₂₉ NO ₄ S) Calculated value: C, 63.30; H, 7.70; N, 3.6
9; S, 8.45 Found: C, 63.07; H, 7.71; N, 3.7.
2; S, 8.30

Example 37 (E) -5- (3,5-di-tert-butyl-4-hydro)
Xy) Benzylidene-2-ethyl-3-hydroxy-
1,2-isothiazolidine-1,1-dioxide 8I
h

[Chemical 34] In a methylene chloride solution (30 ml) of compound 8Ig (870 mg, 2.29 mmol), diisobutylaluminum hydride (DIBA) was added under cooling and stirring at -40 ° C or lower.
L) solution (1.0 M hexane; 4.22 ml) was added dropwise,
After about 5 minutes, a saturated aqueous solution of ammonium chloride (3
0 ml) and the resulting slurry is filtered through Celite,
A saturated aqueous ammonium chloride solution (70 ml) is added to the filtrate, and the mixture is extracted with ethyl acetate (100 ml). The organic layer was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain crude crystals.
Recrystallization from a hexane: ether mixture gave the target compound as colorless columnar crystals. Yield 762 mg (87.2
%). 8Ih: mp 138-141 ° C IR (KBr) cm ^-1 : 3610,3427,296
8,1653,1595,1432,1261,121
4,1147 NMR (d ₆ -acetone) δ: 1.27 (3H, t, J = 7.
0 Hz, CH ₃ ), 1.48 (18 H, s, 2 × B
u ^t ), 3.01 to 3.12 (1H, m, CH), 3.27
(2H, q, J = 7.0 Hz, CH ₂ ), 3.57 (1H,
m, CH), 5.21 to 5.24 (1H, m, CH (O
H)), 5.35 (1H, broad, OH), 7.18 (1
H, t, J = 2.4 Hz, CH), 7.37 (2H, s, A
r-H) Elemental analysis _{(C 20 H 31 NO 4 S} ) Calculated: C, 62.96; H, 8.19 ; N, 3.6
7; S, 8.40 Found: C, 63.05; H, 8.26; N, 3.6.
7; S, 8.33

Example 38 (E) -5- (3,5-di-tert-butyl-4-hydro
Xy) benzylidene-2-ethyl-dihydro-5H-
1,2-isothiazole-1,1-dioxide (8I
i)

[Chemical 35] T of compound 8Ih (342 mg, 0.896 mmol)
2N hydrochloric acid (1 drop) was added to the HF solution (30 ml),
Stir at room temperature for 3 hours. Saturated sodium bicarbonate solution (3
5 ml) was added and the mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with saturated saline (35 ml) and dried over anhydrous sodium sulfate. The crude crystals obtained by distilling off the solvent under reduced pressure were recrystallized from an n-hexane: ether mixed liquid to obtain the target compound as orange columnar crystals. Yield 296 mg (90.8
%). 8Ii: mp 135-137 [deg.] C IR (KBr) cm < ^-1 >: 3608,3472,296.
1,1593,1560,1435,1392,130
0,1212, 1153 NMR (CDCl ₃ ) δ: 1.40 (3H, t, J = 7.2)
_{Hz, CH 3), 1.43 (} 18H, s, 2 × Bu t),
3.52 (2H, q, J = 7.2Hz, CH ₂ ), 5.50
(1H, s, OH), 6.22 (1H, dd, J = 0.8,
6.2 Hz, CH), 6.54 (1H, dd, J = 1.8,
6.2 Hz, CH), 6.84 (1H, broad, CH), 7.
30 (2H, s, Ar- H) Elemental analysis _{(C 20 H 29 NO 3 S} ) Calcd: C, 66.08; H, 8.04 ; N, 3.8
5; S, 8.82 Found: C, 66.53; H, 8.08; N, 3.8.
2; S, 8.68

[0101]

[Chemical 36] Reference Example _{^{1 (R 3 = CH 2 CH}} 2 CH 3) N-n- propyl-1,2-isothiazolidine-1,1
Dioxide (4e) γ-sultone (12.2 gr, 0.1 mol) was added with stirring under ice cooling.
-Propylamine (5.9 gr, 0.1 mol) was added. The contents solidified as the reaction proceeded. Phosphorus oxychloride (10 ml) was added to this solid product, and the mixture was heated under reflux for 2 hours. Residual phosphorus oxychloride was distilled off under reduced pressure. Ether (100 ml) was added to the residue and insoluble materials were filtered off, and the ether layer was dried. It was dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound 4e as a colorless oily substance. This product was in agreement with the standard product obtained in Preparation Example 5. Yield 15.2gr (93%)

Reference Example 2 (R ³ = CH ₂ CH (CH ₃ ) ₂ ) N-isobutyl-1,2-isothiazolidine-1,1-di
Oxide (4c) By the same method as in Reference Example 1, γ-sultone (12.2 gr,
0.1 mol), isobutylamine (7.3 gr, 0.1 mol) and phosphorus oxychloride (10 ml) were reacted to obtain the target compound 4c. This product was in agreement with the standard product obtained in Preparation Example 3. Yield 15.9gr (90%)

The usefulness of the compound I of the present invention prepared in the above Examples as an anti-inflammatory agent was tested in vivo and in vitro. Incidentally, among the control compounds in the following test examples,
E-5110 is N-methoxy-3- (3,5-di-t-
Butyl-4-hydroxybenzylidene) -2-pyrrolidone (described in JP-A-61-257967). Test Example 1 PGE ₂ production inhibitory effect on rat synovial cells LEW / Crj male rats (weight 300-350 g)
The synovial tissue was collected and subcultured under constant conditions to the number of cells required for the experiment. 4x10 ³ cultured synovial cells
/ 160μl / well and put in a 96-well plate,
Cultured in a CO ₂ incubator for 72 hours. afterwards,
20 μl of various concentrations of test drug and 20 μl of human IL-1β
(Final concentration of 30 U / ml) was added at the same time and reacted for 15 hours in a CO ₂ incubator, and the supernatant was stored at −80 ° C. until PGE ₂ measurement. Measurement of PGE ₂ after melting the stored samples was performed by RIA using ¹²⁵ I-PGE _2.
The results are shown in Table 1.

Test Example 2 LTB in rat peritoneal cells
₄ Inhibition of production 0.1% bovine serum albumin (BSA) and 2 were intraperitoneally administered to Jci-SD male rats (weight 300-350 g).
After injecting 10 ml of Hanks' solution containing 5 U / ml heparin, ascites was collected and centrifuged at 1500 rpm for 5 minutes at 4 ° C. Cell fraction (precipitate) containing 0.1% BSA in Hanks'
The cells were suspended in a liquid and adjusted to 1 × 10 ⁶ cells / ml. The adjusted 800 μl (8 × 10 ⁵ cells) of peritoneal cells were transferred to a polypropylene tube, incubated at 37 ° C. for 10 minutes, 100 μl of the test drug at various concentrations was added, and the mixture was further incubated for 10 minutes. Then, add 100 μl of Ca-ionophore A23187 (final concentration 1 μM) to 15
After reacting for a minute, stop the reaction by cooling with ice,
After centrifuging at 0 rpm x 5 minutes, collect the supernatant, and measure -80
Stored at ° C. Measurements of LTB ₄ after melting the stored samples, ³
It was carried out by RIA using H-LTB ₄ . The results are shown in Table 1.

Test Example 3 LPS in THP-1 cells
IL-1 production inhibitory effect under stimulation THP-1 cells were dispersed in RPMI1640, and one well was placed on a 24-well plate, 800 μl of cell suspension (5 × 10 ⁶ cells / ml), 100 μl of test drug at various concentrations, LPS10
The reaction was initiated by adding 0 μl (final concentration 10 μg / ml). After standing at 37 ° C for 24 hours, collect the supernatant and
After centrifuging at 00 rpm × 10 minutes, the supernatant was collected. IL-1
Was measured using ¹²⁵ I-IL-1β.
Conducted in A. The results are shown in Table 1.

[0106]

[Table 1]

Test Example 4 Rat Carrageenin Paw Edema Suppressing Action Method of Winter et al. (Winter, CA. Proc. So
c.Exp.Biol.Med., 111, 54, 1962).
Was improved. That is, LEW / Crj male rats (6 weeks old, weight 140-170 g) were used for 24 days from the day before the experiment.
They were fasted for a period of time and used as one group of 7-8 animals. One hour after the oral administration of the drug, 1% λ-carrageenin (PICININ-A, Z
edema was induced by subcutaneously injecting 0.1 ml of the ushikagaku) solution into the footpad of the right hind leg. Before the carrageenin injection and every 1 hour after the injection, the paw volume of the right hind limb was determined by a volumetric method by the water displacement method. The inhibition rate of the drug administration group to the vehicle administration group was calculated, and the efficacy was determined by Dunnett-t test.
The anti-edema effect of the drug was determined by regression analysis from the inhibition rate 3 or 4 hours after carrageenin administration by ED ₅₀ (mg / K
g) was asked. The results are shown in Table 2.

Test Example 5 Rat gastric mucosal lesion formation inhibitory action LEW / Crj male rats (6 weeks old, body weight 140-1)
60 g) was used as 6 animals per group. The drug was orally administered to the rats fasted for 24 hours from the day before the experiment, and 6 hours later, the animals were killed by exsanguination under ether anesthesia. The stomach was removed, and about 6 ml of physiological saline was enclosed therein, and then immersed in a 1% formalin solution for about 15 minutes. An incision was made along the bay of the stomach, and the damaged state of the gastric mucosa was observed under a real microscope to measure the number of gastric lesions and the length of bleeding spots. As for the degree of disability, the cumulative value of the hemorrhagic spot length of each treatment group was shown as a Lesion Index (mm). Further, the action intensity of the drug was displayed by calculating UD ₅₀ (mg / Kg) by the Probit method from the number of cases of onset corresponding to the dose of each drug. The results are shown in Table 2.

[0109]

[Table 2]

Formulation Example 1 1) Granules Compound 8a 20 mg Lactose 250 mg Corn starch 115 mg Hydroxypropyl cellulose 115 mg Each of the above raw materials is made into granules by a wet method according to a conventional method.

EFFECT OF THE INVENTION PGE ₂ , LTβ ₄ and IL-1 have production inhibitory activity, and anti-inflammatory action is expected.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display location A61K 31/425 ABE 7431-4C 31/44 7431-4C 31/535 7431-4C 31/54 7431- 4C C07D 275/02 279/02 291/04 291/06 327/04 327/06 333/48 335/02 409/04 333 7602-4C 335 7602-4C 417/06 213 9051-4C

Claims (5)

[Claims] 1. Formula I: [In the formula, A is —CH ₂ — or —CH ₂ CH ₂ —; B is
Or represents a bond or _{-CH 2 -, - CHOH -,} - CO
-, -O-, or A and B together form -CH = C
H-may be formed; D is> N- or>
CH-; R ¹ and R ² are each independently hydrogen, lower alkyl or lower alkoxy; R ³ is hydrogen, lower alkyl, cycloalkyl, lower alkoxy; arylalkyloxy, heteroarylalkyloxy, lower alkylcarbonyl, arylcarbonyl, substituted or unsubstituted carbamoyl or _{formula,: - (CH 2) n} -R 4 ( wherein, R ⁴ is hydrogen, hydroxy, substituted or unsubstituted amino, aryl, heteroaryl, hydroxycarbonyl or lower alkyloxycarbonyl Carbonyl; n is 0 to 3
Represents a group represented by) and a compound represented by. 2. The compound of claim 1 wherein R ¹ and R ² are t-butyl. 3. A is --CH _2- , B is --CH _2- , and D is>.
The compound of claim 1 or 2, which is N-. 4. The compound according to claim 1, 2 or 3 wherein R ³ is lower alkyl or cycloalkyl. 5. An anti-inflammatory agent containing the compound of claim 1 as an active ingredient.