KR840000910B1 - Process for preparing sulfonium compounds - Google Patents

Abstract

Sulfonium salts I(R1, R2 = optionally substituted alkyl, Ph, cycloalkyl; m = 1,2; n = 1-15; Y = halo, residue of inorganic or organic acid) were prepd. by reaction of II and III. Thus, methylene(tetrahydro-2-pyranyl)chloride was reacted with MeSH and the thioether quaternized with P - toluene methyl sulfonate to give I(R1 = R2 = Me; m = 1; n = 2; Y =4-MeC6H4SO3, II). At 3.0 mg/kg day i.v. for 10 days II gave 73.3% inhibition of sarcoma 180 in mice.

Description

Process for preparing sulfonium compound

The present invention is a method for producing a sulfonium compound, a pharmaceutical composition containing the compound. It relates to a method of treatment using the composition.

The sulfonium compound according to the present invention is represented by the following general formula (I).

Wherein R ₁ and R ₂ are each alkyl; cycloalkyl; cyclopropylmethyl; alkylene-2-tetrahydrofuranyl; alkylene-2-tetrahydropyranyl; alkenyl, alkyl, alkoxy or halogen Phenyl; aralkyl which may be substituted by alkyl, alkoxy or halogen on the benzene ring; or benzoyloxyethyl, Y ₁ is a halogen or an inorganic acid residue or an organic acid residue, n is 1 degree and 2 is an integer of 1 to 15 .)

In general formula (I), the alkyl group represented by R ₁ and R ₂ or an alkyl group 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, second butyl, tertiary butyl, pentyl, hexyl, octyl and decyl Preferred are straight or branched chain alkyl groups.

In the general formula (I), the cycloalkyl group represented by R ₁ and R ₂ is preferably a cycloalkyl group having 4 to 8 carbon atoms such as cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl.

The alkylene groups constituting the alkylene-2-tetrahydrofuranyl and alkylene-2-tetrahydropyranyl groups represented by R ₁ and R ₂ in General Formula (I) are methylene, ethylene, propylene, trimethylene, tetra Preference is given to having 1 to 6 carbon atoms such as methylene and hexamethylene.

In general formula (I), it is preferable that the alkenyl group represented by R <_1> and R <_2> has 2-10 carbon atoms, such as vinyl, allyl, propenyl, butenyl, hexenyl, octenyl, and decenyl.

In general formula (I), it is preferable that the aralkyl group represented by R <_1> and R <_2> has 1-4 carbon atoms in alkyl site like benzyl, phenyl, and phenylpropyl. The aralkyl group and phenyl group represented by R ₁ and R ₂ in General Formula (I) may have one or more substituents on the benzene ring. Examples of preferred substituents include alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl and isopropyl, alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy and isopropoxy and And halogen atoms such as chlorine, cancellation, and iodine. Examples of preferred phenyl and aralkyl groups having the aforementioned substituents include o-methylphenyl, p-ethylphenyl, p-methoxyphenyl and m-chlorophenyl and o-methylbenzyl, o-ethoxybenzyl, m-chlorobenzyl, p- Bromobenzyl, o-methylphenethyl, p-chlorophenyl, p-propylmethylphenylpropyl, p- and methoxyphenylbutyl.

Examples of preferred groups represented by Y ₁ include halogens, inorganic protonic acid residues and organic protic acid residues, and useful halogens include chlorine, iodine and cancellation, and examples of useful inorganic protic acid residues include nitrates, sulfonates, Phosphates, metaphosphates, and perchlorates are mentioned, and examples of the organic protic acid residues include sulfonic acid residues and carboxyl residues. Examples of preferred euphonic acid residues include p-toluenesulfonate, picrylsulfonate, cyclohexylsulfamate; Camphorsulfonate, benzenesulfonate, 1,5-naphthalene-disulfonate, flavianate and methanesulfonate; examples of preferred carboxylic acid residues are maleate, malonate, fumarate, citrate, lac Laterate, tartrate, ascorbate, linoleate, laurate, palmitate, stearate, oleate, acerate, propionate, butyrate, isobutyrate, valerate, oxalate, succinate, benzoate, nicotine Nate and glycylizate.

Among the compounds represented by the general formula (I), compounds in which at least one of R ₁ and R ₂ is an alkyl group are preferable, m is an integer of 1 to 5, R ₁ and R ₂ are each an alkyl group, and Y ₁ is an organic technique. Particular preference is given to compounds which are residual folic acid.

Preferred compounds according to the present invention prepared in the examples described below in the first fabric are shown below. In Table ₁ , Ts, Pic, and GL in the Y ₁ column represent p-toluenesulfonate, picrylsulfonate, and glycyrizate, respectively.

Exemplary compounds according to the present invention other than the compounds listed in the first table may include the following halogen compounds, inorganic acid salts and organic acid salts of sulfonium compounds.

Methylene (tetrahydro-2-furanyl) dipropylsulfonium

Methylene (tetrahydro-2-furanyl) propylpentylsulfonium

Methylene (tetrahydro-2-pyranyl) methylphenethylsulfonium

Methylene (tetrahydro-2-pyranyl) ethylpropylsulfonium

Methylene (tetrahydro-2-pyranyl) hexyloctylsulfonium

Ethylene (tetrahydro-2-furanyl) methyloctylsulfonium

Ethylene (tetrahydro-2-furanyl) ethylcyclopentylsulfonium

Ethylene (tetrahydro-2-furanyl) ethylcyclohexylsulfonium

Ethylene (tetrahydro-2-furanyl) dihexylsulfonium

Ethylene (tetrahydro-2-furanyl) dibenzylsulfonium

Ethylene (tetrahydro-2-furanyl) dicyclohexylsulfonium

Ethylene (tetrahydro-2-furanyl) diethylsulfonium

Ethylene (tetrahydro-2-furanyl) ethyl-p-chlorophenylsulfonium

Ethylene (tetrahydro-2-furanyl) dipropylsulfonium

Ethylene (tetrahydro-2-furanyl) propylphenethylsulfonium

Ethylene (tetrahydro-2-furanyl) dibutylsulfonium

Ethylene (tetrahydro-2-furanyl) dihexylsulfonium

Ethylene (tetrahydro-2-furanyl) dibenzylsulfonium

Ethylene (tetrahydro-2-furanyl) ethylhexylsulfonium

Propylene (tetrahydro-2-furanyl) dibutylsulfonium

Propylene (tetrahydro-2-furanyl) methylbutylsulfonium

Propylene (tetrahydro-2-furanyl) methylbutylsulfonium

Propylene (tetrahydro-2-furanyl) ethyldesimsulfonium

Propylene (tetrahydro-2-furanyl) ethyl-p-methoxyphenylsulfonium

Propylene (tetrahydro-2-furanyl) hexylcyclopentylsulfonium

Propylene (tetrahydro-2-furanyl) hexylcyclohexylsulfonium

Propylene (tetrahydro-2-furanyl) hexylbenzylsulfonium

Propylene (tetrahydro-2-furanyl) dibenzylsulfonium

Propylene (tetrahydro-2-furanyl) diphenethylsulfonium

Propylene (tetrahydro-2-furanyl) diphenylsulfonium

Propylene (tetrahydro-2-furanyl) phenylbenzylsulfonium

Propylene (tetrahydro-2-pyranyl) diethylsulfonium

Propylene (tetrahydro-2-pyranyl) ethylpropylsulfonium

Propylene (tetrahydro-2-pyranyl) ethyloctylsulfonium

Propylene (tetrahydro-2-pyranyl) dipropylsulfonium

Propylene (tetrahydro-2-pyranyl) dibutylsulfonium

Propylene (tetrahydro-2-pyranyl) butylcyclohexylsulfonium

Propylene (tetrahydro-2-pyranyl) didecylsulfonium

Propylene (tetrahydro-2-pyranyl) dicyclopentylsulfonium

Propylene (tetrahydro-2-pyranyl) cyclopentylcyclohexylsulfonium

Propylene (tetrahydro-2-pyranyl) cyclohexylphenethylsulfonium

Propylene (tetrahydro-2-pyranyl) dibenzylsulfonium

Diethyl-4- (tetrahydro-2-furanyl) butylsulfonium

Dibenzyl-4- (tetrahydro-2-furanyl) butylsulfonium

Ethylcyclohexyl-4- (tetrahydro-2-furanyl) butylsulfonium

Hexylphenyl-4- (tetrahydro-2-furanyl) butylsulfonium

Methyl-3-butenyl-4- (tetrahydro-2-furanyl) butylsulfonium

Dibenzyl-4- (tetrahydro-2-pyranyl) butylsulfonium

Dicyclohexyl-4- (tetrahydro-2-pyranyl) acylsulfonyl

Hexylallyl-4- (tetrahydro-2-pyranyl) butylsulfonyl

Methyl-tert-butyl-5- (tetrahydro-2-furanyl) pentylsulfonium

Dioxyl-5- (tetrahydro-2-furanyl) pentylsulfonium

Benzylphenethyl-5- (tetrahydro-2-furanyl) pentylsulfonium

Dibutyl-5- (tetrahydro-2-pyranyl) pentylsulfonium

Isohexylphenyl-5- (tetrahydro-2-pyranyl) pentylsulfonium

Diphenethyl-5- (tetrahydro-2-pyranyl) pentylsulfonium

Dibenzyl-5- (tetrahydro-2-pyranyl) pentylsulfonium

Ethyl-iso-propyl-6- (tetrahydro-2-furanyl) hexylsulfonium

Methyl (tetrahydro-2-pyranyl) pentyl-6- (tetrahydro-2-furanyl) hexylsulfonium

Dibenzyl-6- (tetrahydro-2-furanyl) hexylsulfonium

Heptylcyclopropylmethyl-6- (tetrahydro-2-pyranyl) hexylsulfonium

Diphenyl-6- (tetrahydro-2-pyranyl) hexylsulfonium

Benzylphenethyl-6- (tetrahydro-2-pyranyl) hexylsulfonium

Diphenethyl-6- (tetrahydro-2-pyranyl) hexylsulfonium

Dimethyl-7- (tetharidro-2-furanyl) heptylsulfonium

Propyloctyl-7- (tetrahydro-2-furanyl) heptylsulfonium

Dicyclopentylmethyl-7- (tetrahydro-2-furanyl) heptylsulfonium

Diethyl-7- (tetrahydro-2-pyranyl) heptylsulfonium

Methylpentyl-7- (tetrahydro-2-pyranyl) heptylsulfonium

Phenylbenzyl-7- (tetrahydro-2-pyranyl) heptylsulfonium

Dipropyl-8- (tetrahydro-2-furanyl) octylsulfonium

Disopropyl-8- (tetrahydro-2-furanyl) octylsulfonium

Methylnonyl-8- (tetrahydro-2-furanyl) octylsulfonium

Ethyl-isohexyl-8- (tetrahydro-2-pyranyl) octylsulfonium

Dioctyl-8- (tetrahydro-2-pyranyl) octylsulfonium

Butylcyclohexyl-8- (tetrahydro-2-pyranyl) octylsulfonium

Butylcyclopentyl-9- (tetrahydro-2-furanyl) nonylsulfonium

Methylphenethyl-9- (tetrahydro-2-furanyl) nonylsulfonium

Propyl (tetrahydro-2-furanylmethyl-9- (tetrahydro-2-furanyl) -nonylsulfonium

Ethyl-m-chlorobenzyl-9- (tetrahydro-2-furanyl) nonylsulfonium

Methyloctyl-9- (tetrahydro-2-pyranyl) nonylsulfonium

Hexylphenyl-9- (tetrahydro-2-pyranyl) nonylsulfonium

Di (tetrahydro-2-furanyl) methyl-9- (tetrahydro-2-pyranyl) -nonylsulfonium

Diethyl-10- (tetrahydro-2-furanyl) decylsulfonium

Ethyl-t-butyl-10- (tetrahydro-2-furanyl) decylsulfonium

Diallyl-10- (tetrahydro-2-furanyl) decylsulfonium

Propyldecyl-10- (tetrahydro-2-pyranyl) decylsulfonium

Diethyl-10- (tetrahydro-2-pyranyl) decylsulfonium

Methylhexyl-10- (tetrahydro-2-pyranyl) decylsulfonium

Octyldecyl-11- (tetrahydro-2-furanyl) undecanylsulfonium

Butylaltyl-11- (tetrahydro-2-furanyl) undecanylsulfonium

Ethyl-p-chlorophenyl-11- (tetrahydro-2-furanyl) undecanylsulfonium

Dibutyl-11- (tetrahydro-2-pyranyl) undecanylsulfonium

Ethyldecyl-11- (tetrahydro-2-pyranyl) undecanylsulfonium

Dibutyl-12- (tetrahydro-2-furanyl) dodecanylsulfonium

Dioctyl-12- (tetrahydro-2-furanyl) dodecanylsulfonium

Cyclopentylcyclohexyl-12- (tetrahydro-2-furanyl) dodecanylsulfonium

Heptyl- (tetrahydro-2-pyranyl) methyl-12- (tetrahydro-2-furanyl) dodecanylsulfonium

Ethylbenzyl-12- (tetrahydro-2-pyranyl) dodecanylsulfonium

Butyldecyl-12- (tetrahydro-2-pyranyl) dodecanylsulfonium

Propyl-p-methoxyphenyl-12- (tetrahydro-12-pyranyl) dodecanylsulfonium

Mesyl-isopropyl-12- (tetrahydro-2-pyranyl) dodecanylsulfonium

Propylcyclopentyl-13- (tetrahydro-2-furanyl) tridecanylsulfonium

Hexyldecyl-13- (tetrahydro-2-furanyl) tridecanylsulfonium

Dicyclohexyl-13- (tetrahydro-2-furanyl) tridecanylsulfonium

Hexylcyclopentyl-13- (tetrahydro-2-pyranyl) tridecanylsulfonium

Butyl-0-methylphenyl-13- (tetrahydro-2-pyranyl) tridecanylsulfonium

Propylbenzoyloxyethyl-13- (tetrahydro-2-pyranyl) tridecanylsulfonium

Butylbenzoyloxyethyl-13- (tetrahydro-2-pyranyl) tridecanylsulfonium

Dibutyl-14- (tetrahydro-2-furanyl) tetrachromanesulfonium

Dinonyl-14- (tetrahydro-2-furanyl) bentadecanylsulfonium

Cyclopentylphenethyl-14- (tetrahydro-2-furanyl) tetradecanylsulfonium

Hexylcyclohexyl-14 (tetrahydro-2-furanyl) tetradecanylsulfonium

Isopentylcyclohexyl-14- (tetrahydro-2-pyranyl) tetradecanylsulfonium

Hexyl-hexyl-14- (tetrahydro-2-pyranyl) tetradecanylsulfonium

Butyl (tetrahydro-2-furanyl) butyl-14- (tetrahydro-2-pyranyl) tetradecanylsulfonium

Dipropyl-14- (tetrahydro-2-pyranyl) tetradecanylsulfonium

Nonyldecyl-15- (tetrahydro-2-furanyl) pentadecanylsulfonium

Butylphenylpropyl-15- (tetrahydro-2-furanyl) pentadecanylsulfonium

Benzylcyclopropylmethyl-15- (tetrahydro-2-furanyl) pentadecanylsulfonium

Hexylbenzyl-15- (tetrahydro-2-pyranyl) pentadecanylsulfonium

Dihexyl-15- (tetrahydro-2-pyranyl) pentadecanylsulfonium

Dimethyl-15- (tetrahydro-2-pyranyl) pentadecanylsulfonium

Dicyclopropylmethyl-15- (tetrahydro-2-pyranyl) pentadecanylsulfonium

Sulfonium compounds represented by general formula (I) are immunostimulatory, anticancer, anti-inflammatory and analgesic, rheumatism, autoimmune, allergy and asthma treatment, stimulating function, infectious action, immunosuppression as side effects. It is useful as an active ingredient of pharmaceuticals and pesticides because it has side effects prevention, immunotherapy, platelet aggregation inhibitory action and plant growth regulation action on compounds such as steroids and anticancer agents.

The compound according to the present invention can be prepared by reacting the method described in the following reaction formula, for example, the sulfide compound represented by the general formula (II) with the compound represented by the general formula (III).

[Reaction A]

Wherein R ₁ , R ₂ , Y, n and m are as defined above.

Useful starting material compounds represented by formula (II) are used in the preparation of compound (I), wherein R ₁ , n and m are sulfide compounds as defined in formula (I). Illustrative of these compounds are as follows.

Methylene (tetrahydro-2-furanyl) methylsulfide

Methylene (tetrahydro-2-furanyl) propylsulfide

Methylene (tetrahydro-2-furanyl) butyl sulfide

Methylene (tetrahydro-2-furanyl) decylsulfide

Methylene (tetrahydro-2-furanyl) cyclopentylsulfide

Methylene (tetrahydro-2-furanyl) phenylsulfide

Methylene (tetrahydro-2-furanyl) benzyl sulfide

Methylene (tetrahydro-2-furanyl) phenethylsulfide

Methylene (tetrahydro-2-pyranyl) methylsulfide

Methylene (tetrahydro-2-pyranyl) ethylsulfide

Methylene (tetrahydro-2-pyranyl) cyclohexylsulfide

Methylene (tetrahydro-2-pyranyl) allyl sulfide

Methylene (tetrahydro-2-pyranyl) phenylsulfide

Ethylene (tethahydro-2-furanyl) methylsulfide

Ethylene (tethahydro-2-furanyl) butyl sulfide

Ethylene (tethahydro-2-furanyl) hexyl sulfide

Ethylene (tethahydro-2-furanyl) phenyl sulfide

Ethylene (tethahydro-2-furanyl) methylphenethylsulfide

Ethylene (tethahydro-2-furanyl) methylsulfide

Ethylene (tethahydro-2-furanyl) butyl sulfide

Ethylene (tethahydro-2-furanyl) benzyl sulfide

Propylene (tetrahydro-2-furanyl) methylsulfide

Propylene (tetrahydro-2-furanyl) ethylsulfide

Propylene (tetrahydro-2-furanyl) propyl sulfide

Propylene (tetrahydro-2-furanyl) decylsulfide

Propylene (tetrahydro-2-furanyl) cyclohexylsulfide

Propylene (tetrahydro-2-furanyl) benzyl sulfide

Propylene (tetrahydro-2-furanyl) methylsulfide

Propylene (tetrahydro-2-furanyl) ethylsulfide

Propylene (tetrahydro-2-furanyl) propyl sulfide

Propylene (tetrahydro-2-furanyl) octyl sulfide

Propylene (tetrahydro-2-furanyl) benzyl sulfide

Methyl-4- (tetrahydro-2-furanyl) butyl sulfide

Nonyl-4- (tetrahydro-2-furanyl) butyl sulfide

(Tetrahydro-2-furanyl) buzyl-4- (tetrahydro-2-furanyl) -butylsulfide

Butyl-4- (tetrahydro-2-pyranyl) butyl sulfide

Cyclohexyl-4- (tetrahydro-2-pyranyl) butyl sulfide

Ethyl-5- (tetrahydro-2-furanyl) pentylsulfide

Allyl-5- (tetrahydro-2-furanyl) pentylsulfide

Isopentyl-5- (tetrahydro-2-pyranyl) pentylsulfide

Phenyl-5- (tetrahydro-2-pyranyl) pentylsulfide

Propyl-6- (tetrahydro-2-furanyl) hexylsulfide

Cyclopentyl-6- (tetrahydro-2-furanyl) hexylsulfide

2-butyl-6- (tetrahydro-2-pyranyl) hexylsulfide

Benzyl-6- (tetrahydro-2-pyranyl) hexylsulfide

Butyl-7- (tetrahydro-2-furanyl) heptylsulfide

Phenyl-7- (tetrahydro-2-furanyl) heptylsulfide

(Tetrahydro-2-pyranyl) propyl-7- (tetrahydro-2-pyranyl) -heptylsulfide

Phenethyl-7- (tetrahydro-2-pyranyl) heptheptylsulfide

Isohexyl-8- (tetrahydro-2-furanyl) octyl sulfide

Benzyl-8- (tetrahydro-2-furanyl) octylsulphide

Octyl-8- (tetrahydro-2-pyranyl) octylsulfide

p-methoxyphenyl-8- (tetrahydro-2-pyranyl) octylsulfide

Decyl-9- (tetrahydro-2-furanyl) nonylsulfide

(Tetrahydro-2-furanyl) ethyl-9- (tetrahydro-2-furanyl) -nonylsulfide

Phenylpropyl-9-tetrahydro-2-pyranyl) nonylsulfide

Cyclohexyl-10- (tetrahydro-2-furanyl) decylsulfide

Ethyl-10- (tetrahydro-2-pyranyl) decylsulfide

(Tetrahydro-2-pyranyl) methyl-10- (tetrahydro-2-pyranyl) -decylsulfide

Butyl-11- (tetrahydro-2-furanyl) undecylsulfide

Benzyl-11- (tetrahydro-2-furanyl) undecylsulfide

Nonyl-11- (tetrahydro-2-pyranyl) undecylsulfide

Hexyl-12- (tetrahydro-2-furanyl) undecylsulfide

Cyclopropylmethyl-12- (tetrahydro-2-pyranyl) dodecanylsulfide

Phenethyl-12- (tetrahydro-2-pyranyl) dodecanylsulfide

Methyl-13- (tetrahydro-2-furanyl) tridecanylsulfide

Cyclohexyl-13- (tetrahydro-2-furanyl) tridecanylsulfide

Benzoyloxymethyl-13- (tetrahydro-2-pyranyl) tridecanylsulfide

o-methylphenityl-14- (tetrahydro-2-furanyl) tetradecanylsulfide

Isopentyl-14- (tetrahydro-2-pyranyl) tetradecanylylsulfide

Hexyl-14- (tetrahydro-2-pyranyl) tetradecanylylsulfide

Octyl-15- (tetrahydro-2-furanyl) pentadecanylsulfide

Methyl-15- (tetrahydro-2-pyranyl) pentadecanylsulfide

Benzyl-15- (tetrahydro-2-pyranyl) pentadecanylsulfide

Sulphide compounds useful as starting materials can be prepared as novel compounds by reacting the following reaction process formulas, for example, the known halides represented by formula (IV) with the known mercaptans represented by formula (V). have.

Wherein R ₁ , n and m are as defined above and Hal represents a halogen atom.

The reaction can be carried out at about 0 to about 200 ° C., preferably at room temperature to about 150 ° C., for about 0.5 to 24 hours, with or without solvent, preferably under the presence of a basic compound. Examples of useful basic compounds include alkali metals such as sodium and potassium; Alkali metal hydrides, such as sodium hydride, potassium hydride, and lithium hydride | Alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide, and normal basic compounds can be mentioned. Examples of useful solvents include alcohols such as methanol, ethanol and butanol; Ethers such as ethyl ether and propyl ether; Polar solvents such as acetonitrile, nitromethane and pyridine; And halogenated hydrocarbons such as dichloromethane (methylene chloride), dichloroethane (ethylene chloride), and chloroform, and aromatic hydrocarbons such as benzene, toluene and xylene, and water. It is preferable to use 1-4 mol of mercaptans represented by general formula (V) with respect to 1 mol of halides represented by general formula (IV). The preparation method of sulfide compound (II) useful as a starting material will be described in detail in the following reference example.

Compounds of general formula (III) and two other starting compounds useful for the preparation of the compounds according to the invention are used for the preparation of compound (I), wherein R ₂ and Y ₁ are known compounds in which general formula (I) is defined to be. Preferred methyl chloride, methyl iodide, ethyl bromide, propyl chloride, cyclopropyl methyl iodide, butyl iodide, butyl bromide, hexyl chloride, cyclohexyl iodide, cyclopropyl methyl bromide, butyl bromide, hexyl chloride, cyclohexyl iodide, Cyclobromyl bromyl, cyclohexyl bromide, cyclopentyl iodide, heptyl iodide, nonyl iodide, decyl bromide, allyl bromide, benzyl chloride, benzyl bromide, octyl iodide, methyl methanesulfonate, ethyl methanesulfonate, p-toluenesulfonic acid methyl p-toluene Nonyl sulfonate, p-toluene sulfonate, butyl p-toluesulfonate, ethyl nicotinate, methyl benzoate, and monomethyl phosphate.

The preparation of the compounds according to the invention is carried out at about −30 to about 150 ° C., preferably at 0 to about 100 ° C. for about 0.5 to about 24 hours with or without solvent. It is preferable to use about 1 to about 4 moles of the compound of the general formula (III) with respect to 1 mole of the sulfide compound of the general formula (II). Examples of useful solvents include alcohols such as methanol, ethanol and propanol; Polar solvents such as acetonitrile, nitromethane, dimethylformamide, dimethyl sulfoxide and pyridine; Chlorinated hydrocarbons such as dichloromethane, dichloroethane and chloroform; Aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as ethyl ether and propyl ether and other acetone, ethyl acetate, petroleum ether, water and the like can be enumerated.

The sulfonium compound represented by general formula (I) can be manufactured as mentioned above. The desired product from the reaction mixture can be isolated by conventional separation operations such as extraction, concentration, distillation, recrystallization or column chromatography.

Among the compounds according to the present invention prepared by the above reaction, the compound represented by the following general formula (I-a) can be converted into another compound according to the present invention represented by the following general formula (I-b) by salt exchange.

The reaction process formula of this method is as follows.

(Reaction C)

Wherein R ₁ , R ₁ , n and m are as defined above, X is a halogen atom, Y ₂ is a halogen atom or an inorganic acid residue or an organic acid residue different from X, and Z is a warm atom or an alkali metal.

In the above-described salt exchange reaction, the sulfonium halide according to the present invention represented by the general formula (I-a) can be used either as a sieve contained in the reaction mixture resulting from the above reaction (reaction A) or as a body isolated from the reaction mixture.

As the mixture represented by the general formula (IV), compounds which can be the Y ₂ group of the general formula (Ib) are useful, and examples of these compounds include inorganic acids and silver silver or alkali metal salts. Suitable halogen compounds include chlorides, sucrose and on-oxides, and examples of suitable inorganic acids include nitric acid, sulfuric acid, phosphoric acid, metaphosphoric acid and superphosphoric acid. Malonic acid, fumaric acid, citric acid, lactic acid, tartaric acid, lauric acid, palmitic acid, stearic acid, linoleic acid, oleic acid, fish acid, succinic acid, flavinic acid, camphor-sulfonic acid, ascorbic acid, cyclohexylsulfonic acid, methanesulfonic acid , Benzenesulfonic acid, p-toluenesulfonic acid, picrylsulfonic acid, benzoic acid, nicotinic acid, glycyrrhetinic acid, glycyrrhizin, 1,5-naphthalene disulfonic acid, and the like. Examples of the alkali metal salts of the inorganic and organic acids described above are sodium Salts, potassium salts and lithium salts can be enumerated.

The reaction can be carried out in about 0.5 to about 24 hours in a solvent at a temperature of about -30 to about 150 ° C, preferably about 0 to about 100 ° C. The compound represented by the general formula (IV) is preferably used in an amount of about 1 to 4 times the theoretical amount relative to the sulfonium halide represented by the general formula (I-a). As a solvent of this reaction, all the solvents already described by reaction (reaction A) mentioned above can be used.

The above-described salt exchange reaction is also performed by the sulfonium halide represented by the following general formula (VIII) obtained by reacting the sulfonium halide represented by the general formula (Ia) with the silver oxide represented by the following general formula (VII). It can also be performed by the following reaction characterized by producing the target sulfonium compound (Ib) by reacting with the compound represented by general formula (IX).

Wherein R ₁ , R ₂ , X, Y ₂ , n and m are as defined above.

Illustrative useful compounds represented by the general formula (IX) include the organic or inorganic acids of glass already described in the above reaction (reaction-C). The method may be carried out by injecting a sulfonium halide represented by the general formula (Ia), a silver oxide (VII) and a compound represented by the general formula (IX) simultaneously with a suitable solution, but first, a sulfonium halide. It is preferable to employ a second stage method of reacting silver peroxide with a sulfonium hydroxide represented by the general formula (VIII) as an intermediate, and then introducing compound (IX) into the reaction system to react with the intermediate again.

About 1 mol or more normally, Preferably about 1 to about 1 mol with respect to 1 mol of sulfonium halides (Ia) which uses silver (VII) as a starting material for manufacture of the sulfonium hydroxide represented by general formula (VIII). Can be used in 4 moles. The compound represented by the general formula (IX) may be used in an amount of about 1 mole or more, preferably about 1 to about 4 moles, per 1 mole of sulfonium halide (I-a) used as a starting material. As a solvent of this reaction, the same solvent already described in reaction (reaction C) mentioned above can be used. The reaction of sulfonium halide (Ia) with ion (VII) and the reaction of sulfonium hydroxide (VIII) obtained as an intermediate in the first reaction with a compound represented by formula (IX) are usually about -30 to about 150 ° C., preferably about 0 to about 100 ° C. and about 0.5 to 24 hours, respectively.

After the heat exchange reaction is completed, the target object I-b can be isolated by the same method as described above in the above reaction (reaction A).

When the compound according to the present invention is used as a drug, it may be prepared in various formulations such as oral, injectable or rectal suppositories depending on the therapeutic purpose. The above-mentioned formulation form can be manufactured by a well-known method. In the case of solid oral preparations such as tablets, dragees, granules, powders and capsules, excipients, binders, disintegrants, lubricants and lubricants may be added to the compounds according to the invention. Such additives are already known in the art and include useful excipients such as lactose, white sugar, sodium chloride, glucose solution, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, and binders include water, ethanol, Propanol, glucose, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and polyvinylpyrrolidone may be exemplified, and as a disintegrant, dry starch, sodium alginate, agar powder, sodium hydrogencarbonate, calcium carbonate, sodium lauryl sulfate, Glyceryl monostearate, starch and lactose can be enumerated, and examples of the lubricant or lubricant include purified talc, stearic acid salt, boric acid powder solid polyethylene glycol, and the like. If necessary, colorants, preservatives, flavorings, seasonings, sweeteners and the like may be added to the solid preparations in addition to other pharmaceuticals. In the case of liquid preparations for oral administration, such as liquids, granules and dry syrups, excipients and, if desired, seasonings, buffers, stabilizers and the like can be added to the compounds according to the invention. In the case of preparations of parenteral solutions. Modulators, buffers, stabilizers, local anesthetics, and the like can be added to the compounds according to the invention and administered subcutaneously, intramuscularly, or intravenously. Excipients for rectal suppositories; A suppository may be administered rectally by adding a surfactant or the like to the compound according to the present invention.

The amount of sulfonium compound to be blended in the above-mentioned formulations varies depending on the condition of the patient and the method of preparation.However, about 5 to about 1000 mg dosage unit for oral administration, about 0.5 to about 500 mg dosage unit for parenteral administration. And in the case of rectal administration, about 5 to about 1000 mg dosage unit is preferred. The daily dose for adults depends on the condition, but from about 0.5 to about 5000 mg is preferred for commercial use.

In the following, reference is made to the preparation of the starting compounds used in the preparation of the compounds according to the invention and the preparation examples of the compounds according to the invention. The number of a compound in an Example corresponds to the number of the compound described in the following 1st table | surface. The properties and yields of the compounds in the examples are set forth in the following Tables 2 and 3. In the case of oil in these compounds, the NMR values measured in DMSO-d ₆ using TMS as the internal standard are listed in Table 2, and other compounds (including some of the compounds listed in Table 2) are oily. In the case of water, it is shown in Table 3 as a ″-″ mark in the melting point column.

Reference Example 1

50 g of methyl mercaptan was added to 100 ml of an aqueous 18% sodium hydroxide solution, and 50 g of methylene (tetrahydro-2-pyranyl) chloride was added thereto to reflux for 5 hours, followed by cooling. The reaction mixture was extracted with methylene chloride, the methylene chloride layer was separated, washed with water and dried over anhydrous sodium sulfate.

The resulting mixture was distilled off to give 37.5 g (yield 69.1%) of methylene (tetrahydro-2-pyranyl) methylsulfide having a boiling point of 69 to 70 ° C / 100 mmHg.

Reference Example 2

14 g of sodium metal was dissolved in 350 ml of methanol, and 63 g of methyl mercaptan was added to the solution, followed by 75 g of ethylene (tetrahydro-2-furanyl) chloride. The mixture was refluxed for 5 hours, cooled and filtered. The filtrate was distilled to 6.6 g (yield 93.7%) of ethylenete (trahydro-2-furanyl) methylsulfide having a boiling point of 113 ° C./33 mmHg.

Reference Example 3

0.5 g of sodium metal, 2.8 g of n-octylmercaptan and 3 g of 5- (tetrahydro-2-pyranyl) -n-pentyl chloride were added to 50 ml of methanol and the mixture was heated at 60 to 70 ° C. for 4 hours. . The reaction mixture was distilled off to remove the solvent, and water and chloroform were added to the residue to extract. The chloroform layer was distilled to obtain 4.5 g (95.4%) of n-octyl-5- (tetrahydro-2-pyranyl) pentyl sulfide having a boiling point of 160 to 163 ° C / 2 to 3 mmHg.

Reference Example 4

To 210 ml of 10% aqueous calcium hydroxide solution, 25 g of methyl mercaptan and 71 g of 4- (tetrahydro-2-furanyl) butyl bromide were added, followed by stirring at room temperature for 8 hours. The reaction mixture was distilled off and the solvent was distilled off, and then treated in the same manner as in Reference Example 3 to obtain methyl-4- (tetrahydro-2-furanyl) -butylsulphide having a boiling point of 101 to 102 ° C./4 to 5 mmHg. g (93.9%) was obtained.

Example 1

15 g of methylene (tetrahydro-2-pyranyl) methyl sulfide and 38 g of methyl p-toluene sulfonate were added to 70 ml of ether, and it stirred at room temperature for 8 hours. The insolubles were filtered off and recrystallized from acetonitrile-ether to give 32.1 g (yield 93.9%) of methylene (tetrahydro-2-pyranyl) -dimethylsulfonium p-toluenesulfonate (Compound 50).

Example 2

1-.2 g of ethylene (tetrahydro-2-furanyl) methylsulfide and 19 g of methyl p-toluenesulfonic acid were stirred at room temperature for 6 hours, ether was added thereto, and the insolubles were filtered off to form methylene chloride-. Recrystallization from ether gave ethylene (tetrahydro-2-furanyl) dimethylsulfonium p-toluenesulfonate (Compound 29).

Example 3

1,12, 19,21,23,42,44,46,58 and 63 were prepared by following the same 4 methods as in Example 2 using the appropriate starting materials.

Example 4

Dissolve 3.2 g of methylene (tetrahydro-2-pyranyl) ethylsulfide in 30 ml of methylene chloride, firstly add 6.0 g of ethyl iodide, then add 5.6 g of p-toluenesulfonic acid at room temperature for 8 hours. Stirring was performed. The reaction mixture was filtered, hydrogen sulfide and activated carbon were added to the filtrate, and the filtrate produced after filtration was concentrated. The concentrated solution was purified by methylene chloride-ether to obtain 6.3 g (yield 93.8%) of methylene (tetrahydro-2-pyranyl) dimethylsulfonium p-toluenesulfonate (Compound 52).

Example 5

Compounds 17,18,25,27,40,41,45,48,54,56,59 and 61 were prepared by following the same method as Example 4 with the appropriate starting materials.

Example 6

To the aqueous solution in which 9.5 g of methylene (tetrahydro-2-furanyl) dimethylsulfonium p-toluenesulfonate was dissolved in water, 12.6 g of sodium picrylsulfonate was added. The resulting crystals were recrystallized with ethanol to obtain 12.5 g (yield 95%) of methylene- (tetrahydro-2-furanyl) dimethylsulfonium picrylsulfonate (compound 2).

Example 7

Compounds 13,15,20,22,24,29,28,39,43,49,53,55,57,60 and 62 were prepared by following the same method as Example 6 with the appropriate starting materials.

Example 8

A mixture of 13.2 g of methylene (tetrahydro-2-furanyl) methyl sulfide and 30 g of methyl iodide was stirred at room temperature for 3 hours. Ether was added to the reaction mixture, the insolubles were filtered off, and then purified by acetonitrile-ether to obtain 26 g (yield 95.6%) of methylene (tetrahydro-2-furanyl) dimethylsulfonium iodide (Compound 3).

Example 9

Compounds 16,30 and 31 were prepared by repeating the same method as in Example 8 using the appropriate starting material.

Example 10

13.2 g of methylene (tetrahydro-2-furanyl) dimethylsulfonium iodide and 15.7 g of cyclohexyl sulfamic acid were added to 200 ml of ethanol, followed by stirring for 2 hours. The reaction mixture was filtered, hydrogen sulfide was added to the filtrate and treated with activated carbon. The mixture was filtered, and the concentrate obtained by concentrating the filtrate was recrystallized in ethanol-ether to obtain 15.4 g (yield 90.5%) of methylene (tetrahydro-2-furanyl) dimethylsulfonium cyclohexylsulfamate (Compound 14).

Example 11

Compounds 5-10,32-36,47 and 51 were prepared by repeating the same method as in Example 10 using the appropriate starting materials.

Example 12

9.8 g of ethylene (tetrahydro-2-furanyl) dimethylsulfonium chloride and 17 g of cyclohexylsulfonic acid were added to 60 ml of acetonitrile and treated for 3 hours at room temperature. The reaction mixture was then treated in the same manner as in Example 10 to give 15.6 g (yield 92%) of ethylene (tetrahydro-2-furanyl) dimethylsulfoniumcyclohexylsulfamate (Compound 37).

Example 13

18.3 g of methylene (tetrahydro-2-furanyl) methyl-n-decylsulfonium iodide was dissolved in 150 ml of acetonitrile, and 13 g of p-toluenesulfonic acid was added thereto, followed by stirring at room temperature for 3 hours. The produced precipitate was filtered off, hydrogen sulfide was added to the filtrate, and the produced precipitate was filtered off. The resulting filtrate was concentrated and the concentrate was purified by methylene chloride-ether to give 18.6 g (yield 91.6%) of methylene (tetrahydro-2-furanyl) methyl-n-decylsulfonium p-toluenesulfonate (Compound 14).

Example 14

13.7 g of ethylene (tetrahydro-2-furanyl) dimethylsulfonium iodide was dissolved in 400 ml of methanol, and 41.2 g of silver oxide was added thereto, stirred at room temperature for 4 hours, and then filtered.

Next, a solution in which 41.2 g of glycyrrhisin was dissolved in 300 ml of methanol was added to the filtrate, and the concentrate was concentrated. ) 42g (yield 89.9%) was obtained.

Example 15

26 g of methylene (tetrahydro-2-furanyl) dimethyl sulfonium iodide was dissolved in 400 ml of methanol, and 23 g of silver oxide was added thereto, stirred at room temperature for 4 hours, and filtered. A solution in which 10 g of lactic acid was dissolved in 50 ml of methanol was added to the filtrate and concentrated, and the concentrate was recrystallized from methanol-ether to obtain 20 g of methylene (tetrahydro-2-furanyl) dimethylsulfonium lactate (Compound 6).

Example 16

13 g of methylene (tetrahydro-2-furanyl) dimethyl sulfonium iodide was dissolved in 800 ml of methanol, 41.2 g of silver oxide was added thereto, stirred at room temperature for 4 hours, and then filtered. A solution in which 41.2 g of glycyrrhisin was dissolved in 400 ml of methanol was added to the filtrate and concentrated to recrystallize the concentrate from chloroform-ether to obtain methylene (tetrahydro-2-furanyl) dimethylsulfonium glycyrizate (Compound 11).

Example 17

8.7 g of methyl-4- (tetrahydro-2-furanyl) butyl sulfide and 20 g of methyl p-toluenesulfonate are stirred at room temperature for 2 days, and ether is added thereto to filter out the insoluble matter, followed by ethanol ether Recrystallization gave 17.0 g (yield 94.5%) of dimethyl-4- (tetrahydro-2-furanyl) butylsulfonium p-toluenesulfonate (Compound 64).

Example 18

Compounds 69,100 and 116 were prepared by repeating the same method as in Example 17 with the appropriate starting material.

Example 19

12.4 g of 2-benzoyloxyethyl-4- (tetrahydro-2-furanyl) butyl sulfide and methyl p-toluenesulfonic acid were stirred at room temperature for 3 hours, and ether was added thereto to remove insoluble materials, followed by chlorination. Recrystallization from methylene-ether gave 16.9 g (yield 84.9%) of 2-benzoyloxyethylmethyl-4- (tetrahydro-2-furanyl) butylsulfonium p-toluenesulfonate (Compound 73).

Example 20

Compound 68,92,94,104,120, was prepared by repeating the same method as in Example 19 using the appropriate starting material.

Example 21

To 50 ml of ethanol, 2.64 g of benzyl-5- (tetrahydro-2- (furanyl) pentyl sulfide and 40 g of ethyl p-toluene sulfonate were added and heated at 50 to 60 ° C. for 7 hours. The tanol was distilled off, an ether was added to the residue to separate the insolubles, and then purified by methylene chloride-ether to be benzylethyl-5- (tetrahydro-2-furanyl) pentylsulfonium p-toluenesulfonate (oil). Compound 76).

Example 22

Compounds 74, 89, and 111 were prepared in the same manner as in Example 21 using the appropriate starting material.

Example 23

To 50 ml of dimethylformamide, 4.32 g of ethyl-6- (tetrahydro-2-furanyl) hexyl sulfide and 4.5 g of ethyl nicotinate were added and heated at 70 to 80 ° C. for 6 hours. The reaction mixture was distilled off, the solvent was distilled off, and ether was added to the residue. The insolubles were separated and purified with methylene-ether to give 5.6 g (yield 76.3%) of diethyl-6- (tetrahydro-2-furanyl) hexylsulfonium nicotinate as an oil.

Example 24

1.0 g of methyl-5- (tetrahydro-2-pyranyl) pentyl sulfide and 1.5 g of methyl iodide were added to 10 ml of methylene chlorides, and it stirred at room temperature for 7 hours. Ether was added to the reaction mixture, the insolubles were separated, and then purified by methylene chloride-ether to give 1.6 g of dimethyl-5- (tetrahydro-2-pyranyl) pentylsulfonium iodide (compound 110) (yield 94.1%). )

Example 25

Compounds 65,70,78,81,82,84,87,90,91,97,101,105,107,113,121,122,123,127,128 and 131 were prepared by repeating the same method as in Example 24 using suitable starting materials.

Example 26

8.7 g of methyl-4- (tetrahydro-2-furanyl) butyl sulfide, 10.8 g of lactic acid and 14.2 g of methyl iodide were added to 100 ml of acetonitrile and stirred for 8 hours at room temperature. The reaction mixture was filtered, hydrogen sulfide was added to the filtrate, and the filtrate was concentrated. The concentrate was purified by methylene chloride-petroleum ether to give 12.5 g (yield 90%) of dimethyl-4- (tetrahydro-2-furanyl) butylsulfonium lactate (Compound 67).

Example 27

Compound 66, 72, 77, 86, 88, 93, 95, 96, 98, 103, 109, 115, 117, 118, 119, 124, by repeating the same method as in Example 26 with a suitable starting material 125, 126, 129, 130, 132 and 133 were prepared.

Example 28

4.14 g of butylpropyl-5- (tetrahydro-2-pyranyl) pentylsulfonium iodide and 3.1 g of p-toluenesulfonic acid were added to 100 ml of nitromethane, and it stirred at 40-50 degreeC for 3 hours. The reaction mixture was filtered and the precipitate formed by adding hydrogen sulfide to the filtrate was filtered off. The filtrate was concentrated and the concentrate was purified by methylene chloride-ether to give butylpropyl-5- (tetrahydro-2-pyranyl) -pentylsulfonium p-toluenesulfonate (Compound 112) 4.2 g) yield 91.7%).

Example 29

Compounds 71,79,99 and 102 were prepared by repeating the same method as in Example 28 using the appropriate starting material.

Example 30

To 50 ml of ethanol, 435 g of dibenzyl-5- (tetrahydro-2- (furanyl) pentylsulfonium bromide and potassium p-toluenesulfonate 3.3 were added, followed by stirring at room temperature for 6 hours. The resulting oily product was purified with methylene chloride-ether to obtain 4.3 g (yield 81.7%) of dibenzyl-5- (tetrahydro-2-furanyl) -pentylsulfonium p-nium toluenesulfonate compound 80). .

Example 31

Prepared in the same manner as in Example 30 using the appropriate starting material.

Example 32

8.9 g of ethylmethyl-5- (tetrahydro-2-furanyl) pentylsulfonium bromide and 8.3 g of silver oxide were added to 200 ml of methanol, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was filtrated and 6.5 g of cyclohexylsulfonic acid was added to the filtrate, and then the solvent was removed. The residue was purified with ethylene chloride-ether to give 10.8 g (90.8%) of ethylmethyl-5- (tetrahydro-2-furanyl) -pentylsulfonium cyclohexylsulfamate (Compound 75).

Example 33

Compounds 83,108 and 114 were prepared by repeating the same method as in Example 32 using the appropriate starting material.

In the following, pharmaceutical preparations containing a compound according to the present invention will be described.

Formulation Example 1 Tablet

Tablets having the following composition (100 mg per tablet) were prepared.

Formulation Example 2: Capsule

Capsules having the following composition (100 mg per capsule) were prepared.

Formulation Example 3: Granulation

A granule having the following composition (1000 mg per packet) was prepared.

Formulation Example 4 Granules

Granules having the following composition (1000 mg per packet) were prepared.

Formulation Example 5: Syrup

A syrup (50 ml) having the following composition was prepared.

Formulation Example 6: Suppositories

Suppositories with the following composition (8.5 g per one) were prepared.

Compound 29 1.0 g

7.5g fatty acid glycerides

(The Federal Republic of Germany dynamite novel, brand name `` Witepsol W-35 ''

Formulation Example 7 Injection

The composition of the firearm (1 ml per ampoule) was prepared by injection.

Compound 28

Sodium chloride 8mg

Distilled water for injection. . 1ml

A quick test was conducted on the compound according to the present invention to obtain the following results.

(1) Common gene Meth-A antitumor against tumors Male BALB / C mice (weight, 25-30 g) consisting of 10 rats were subcutaneously inoculated with 2 × 10 ⁴ Meth-A cells. The pharmacological saline solution was administered intravenously to the compound according to the present invention at the dosages described in Table 4 below once daily for 7 days from the day following tumor inoculation. Mice were killed 17 days after the inoculation and the tumor was weighed.

Inhibition of the compound according to the present invention on the growth of Meth-A cells was described in Table 4, with the tumor weight of the treated mice divided by the tumor weight of the control mice as the growth inhibition rate.

(2) antitumor activity against sarcoma 180

Male ICR mice (weight, 30-35 g) consisting of 10 rats were subcutaneously inoculated with 5 × 10 ₅ sarcoma cells. The pharmacological saline solution of the compound according to the present invention was administered intravenously at the dosages described in Table 5 below once daily for 10 days from the day following tumor narrowing. Mice were killed 17 days after tumor inoculation and the tumor weighted.

The inhibitory effect of the compounds according to the invention on the growth of sarcoma 180 was measured and the inhibition rates are listed in Table 5.

(3) Anti-tumor action against transplanted tumors with 3-methylcholanthene

Implantable fibrosarcoma 5 × 10 ⁴ or 1 × 10 ⁵ subcutaneous subcutaneous in which C57BL / 6 strains were sensitized with male C57BL / 6 mice (weight, 20-25 g) consisting of 10 animals in group 1 Inoculation. The pharmacological saline solution of the compound according to the present invention was administered intravenously at the dosages described in Table 6 below five times a day from the day after tumor inoculation. Mice were killed 21 days after tumor inoculation and the tumor weighted.

The inhibitory effect of the compounds according to the invention on transplanted fibrosarcoma sensitized with 3-methylcholanthrene was measured and growth inhibition rates are described in Table 6 below.

(4) humoral response effect

On day 1, 1 × 10 ⁷ quantitative blood cells were injected intravenously into mice (group 25 to 30 g body weight) consisting of 10 BALB / C rats. Pharmacological saline solution of the compound according to the present invention was intraperitoneally injected at the dosages described in Table 7 below from day 1 onwards.

On day 5, the number of splenic hemolytic spot-forming cells was counted by Jerne et al. (Science, 140, 405, 1963) by Cunningham et al. (Immunology 14,599, 1968).

As shown in Table 7, Compound 1 according to the present invention can be seen that the number of hemolytic spot cells significantly increased at the dose of 2.5 mg / kg and 40 mg / kg.

(5) Effect on cell mediated immune response

Using BALB / C mice (weight, 20-25 g) consisting of 10 groups of 1 group, cut the abdominal skin with scissors and immunize the mice with 0.1 ml of 7% picryl chloride anhydrous alcohol on the first day, On day 7, 0.02 ml of 1% picric chloride olive oil was immunized in the ear. After 24 hours, ears were measured with a dial gauge. An aqueous solution of the compound according to the invention was orally administered at the dosages listed in Table 8 below on day 1 for seven days from day one. From the results in Table 8, it can be seen that Compound 1 and Compound 29 increase the sensory hypersensitivity response delay.

(6) Rapid Toxicity Test

20 g of body weight was used to intravenously inject pharmacological saline solution of the compound according to the present invention using male mice. The 50% lethal dose of the mice was measured by the up-down method and the results are shown in Table 9 below.

Claims (1)

A method for producing a sulfonium compound represented by the following general formula (I), wherein the sulfide compound represented by the following general formula (II) is reacted with a compound represented by the following general formula (III).

Wherein R ₂ and Y ₁ are each phenyl substituted with alkyl, cycloalkyl, cyclopropylmethyl, alkylene-2-tetrahydrofuranyl, alkylene-2-tetrahydropyranyl, alkenyl, alkyl, alkoxy or halogen, respectively , Aralkyl which can be substituted by alkyl, alkoxy or halogen on the benzene ring, or benzoyloxyethyl, Y ₁ is a halogen or an inorganic acid residue or an organic acid residue, n is 1 or 2, m is an integer of 1-15.