JPS649982B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel sulfonium compounds. The sulfonium compound of the present invention is represented by the following general formula []. RO(CH ₂ ) _o+ S R ₁ R ₂・Y ^- [] [In the formula, R is naphthyl, cycloalkyl, cyclopropylmethyl, tetrahydronaphthyl, indanyl, adamantyl, alkylene-2-tetrahydrofuranyl or as a substituent alkyl,
Indicates a phenyl group that may have at least one selected from alkenyl, alkoxy, acyl, acylamino, halogen, trihalogenomethyl, carboxyl, hydroxyl, amino, nitro, and cyano group. R ₁ and R ₂ are the same or different, and are alkyl, cycloalkyl, alkenyl, phenyl, cyclopropylmethyl, alkylene-2-tetrahydrofuranyl, alkylene-
2-tetrahydropyranyl or an aralkyl group which may have halogen, carboxyl or hydroxyl groups as substituents. n is 2~
The integer 15 and Y represent inorganic acid residues or organic acid residues other than hydrohalic acid. ] Among the substituents that the phenyl group defined by R in the above general formula [] may have, examples of the alkyl group include those having 1 to 6 carbon atoms such as methyl, ethyl, n-hexyl, i-propyl, and t-butyl. The alkenyl group is an alkenyl group having 2 to 4 carbon atoms such as vinyl, allyl, butenyl, etc., and the alkoxy group is an alkenyl group having 1 to 4 carbon atoms such as methoxy, ethoxy, sec-butoxy, i-pentyloxy, etc. 6, the acyl group is acetyl, propanoyl, etc., the acylamino group is acetylamino, butyrylamino, etc., the trihalogenomethyl group is trichlormethyl,
Trifluoromethyl and the like can be mentioned. In addition, the cycloalkyl group defined by R in the general formula [] includes cyclopentyl, cyclohexyl, etc., and the alkylene-2-tetrahydrofuranyl group includes, for example, 1-(tetrahydro-2
-furanyl)-methyl, 2-(tetrahydro-2
-furanyl)-ethyl, 3-(tetrahydro-2
-furanyl)-propyl and the like. The alkyl group defined by R ₁ and R ₂ in the general formula [] is, for example, an alkyl group having 1 to 10 carbon atoms, the cycloalkyl group is, for example, cyclopentyl, cyclohexyl, cycloheptyl, etc., and the alkenyl is, for example, having a carbon number of 1 to 10. For example, an alkenyl group having 2 to 4 carbon atoms, an aralkyl group having 7 to 7 carbon atoms,
10 benzyl, phenethyl, phenylpropyl, etc., and examples of alkylene-2-tetrahydrofuranyl and alkylene-2-tetrahydropyranyl groups include alkylene having 1 to 6 carbon atoms,
Tetrahydrofuran or tetrahydropyran-substituted groups specifically include 1-(tetrahydro-2-furanyl)-methyl, 2-(tetrahydro-2-furanyl)-ethyl, 3-(tetrahydro-2- Furanyl)-propyl and the like. The group defined by Y in the general formula [] is typically, for example, phosphate, metaphosphate, perchlorate, nitrate, sulfate, methanesulfonate, tosylate, picrylsulfonate, camphorsulfonate, 1,5
- naphthalene disulfonate, acetate, maleate, malonate, fumarate, titrate,
Inorganic acid residues and organic acid residues such as lactate, tartrate, ascorbate, linoleate, oleate, stearate, propionate, benzoate, nicotinate, glycyrrhizate, cyclohexyl sulfamate, flavianato, etc. are mentioned. The sulfonium compound of the present invention has antiallergic and antirheumatic effects, and is extremely useful as a pharmaceutical product that utilizes these effects. In addition to the above, the compounds of the present invention also have effects such as enhancing the immune function of the living body, anticancer activity, immunomodulatory activity; anti-inflammatory and analgesic effects; liver function improving activity; anti-autoimmune activity; anti-asthmatic activity; infection-preventing activity; steroid Prevention of side effects of compounds that have immunosuppressive effects as side effects of drugs, anticancer drugs, etc.; auxiliary action for immunotherapy; platelet aggregation inhibition action;
It has biological growth regulating effects and is useful as medicines and agricultural chemicals. The method for producing the compound of the present invention will be explained below. The compound of the present invention can be produced, for example, by the following method. [Production method A] A sulfide compound represented by the general formula RO(CH ₂ ) _o SR ₁ [] (wherein R, R ₁ and n have the same meanings as above) and the general formula
R ₂ Y (In the formula, R ₂ and Y have the same meanings as above.)
React with the compound represented by This reaction is carried out in a solvent or without a solvent at -30 to 150°C.
The reaction is preferably carried out at a temperature of 0 to 100°C for a reaction time of about 0.5 to 72 hours. The compound R ₂ Y may be used in an excess amount relative to the sulfide compound [], but it is preferably used in an amount of about 1 to 4 times the theoretical amount.
Solvents include alcohols such as methanol, ethanol and propanol, polar solvents such as acetonitrile, nitromethane, dimethylformamide and dimethyl sulfoxide, halogenated hydrocarbons such as methylene chloride and chloroform, benzene,
Aromatic hydrocarbons such as toluene and xylene, ethers such as ethyl ether and propyl ether,
Others acetone, petroleum ether, ethyl acetate,
Water and a mixed solvent of these solvents can be used. [Manufacturing _method B] General formula RO(CH ₂ ) _o+ S R _{1 R 2} ) is reacted with a compound represented by the general formula ZY (wherein Z is a silver atom or an alkali metal, and Y has the same meaning as above). Examples of the halogen atom (X) constituting the sulfonium halide represented by the general formula [] include chloride, bromide, and iodide. The compound represented by the general formula ZY is preferably nitric acid, perchloric acid, phosphoric acid, metaphosphoric acid, acetic acid, isobutyric acid, maleic acid, malonic acid, fumaric acid, citric acid, lactic acid, tartaric acid, stearic acid, palmitic acid. , linoleic acid, oleic acid, ascorbic acid, cyclohexylsulfamic acid, methanesulfonic acid, benzenesulfonic acid, tosylic acid, picrylsulfonic acid, benzoic acid, nicotinic acid, glycyrrhesinic acid, glycyrrhizin, camphorsulfonic acid, 1, Examples include silver salts and alkali metal salts such as 5-naphthalenedisulfonic acid. Examples of alkali metals include sodium, potassium, and lithium. This reaction is carried out in a solvent at -30 to 150°C, preferably 0 to 100°C, for a reaction time of usually 0.5 to 72 hours. The compound represented by the general formula ZY may be used in an excess amount with respect to the sulfonium halide represented by the general formula [ ], but is preferably used in an amount of 1 to 4 times the theoretical amount. As the solvent, any solvent that can be used in the reaction of Production Method A can be used. [Production method C] A sulfonium halide represented by the general formula [] is reacted with silver oxide and a compound represented by the general formula HY (Y has the same meaning as above). As the compound represented by the general formula HY, any of the inorganic acids and organic acids exemplified in Production Method B can be used. The amounts of silver oxide and HY to be used may be in excess of the sulfonium halide [], but are preferably 1 to 4 times the theoretical amount by molar amount. As the reaction solvent, any solvent that can be used in production method A can be used. The reaction temperature conditions may be the same as in production method A. The sulfonium compound of the present invention can be easily isolated by commonly known isolation methods such as recrystallization and column chromatography. When using the compound of the present invention as a medicine, various dosage forms can be adopted depending on the therapeutic purpose, such as oral preparations, injection preparations, rectal suppositories, and inhalation preparations. Isodosage forms can be prepared by conventional formulation methods known to those skilled in the art. When preparing a solid preparation for oral use, after adding an excipient, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, etc. to the compound of the present invention, the compound is prepared by a conventional method. Tablets, coated tablets, granules, powders, capsules, etc. can be made. When preparing oral liquid preparations, oral liquid preparations, syrups, etc. can be prepared by adding flavoring agents, buffering agents, stabilizers, flavoring agents, etc. to the compound of the present invention and using conventional methods. When preparing an injection, the compound of the present invention may be added with a PH adjusting agent, a buffering agent,
Subcutaneous, intramuscular, and intravenous injections can be prepared by adding stabilizers, tonicity agents, local anesthetics, and the like by conventional methods. When preparing rectal suppositories, suppositories can be produced by a conventional method after adding an excipient and, if necessary, a surfactant and the like to the compound of the present invention. When preparing an inhalant, an excipient, a propellant, etc. may be added to the compound of the present invention as required, and the inhalant can be manufactured by a conventional method. The amount of the compound of the present invention to be incorporated into the above dosage unit form varies depending on the condition or dosage form, but is generally about 10% per oral dosage unit form.
~1000mg, 1-500mg for injections, 5-500mg for suppositories
500mg, preferably 1-500mg for inhalers. Further, the daily dosage cannot be determined unconditionally depending on the symptoms, etc., but it is usually preferably 1 to 2000 mg. Next, in order to further explain the present invention, reference examples and examples will be shown. The compounds of the present invention obtained in each example and their properties are shown in Table 1 below. Table 1
Medium, Tso, and Pic indicate the following anions. Tso: anion of p-toluenesulfonic acid Pic: Anion of picrylsulfonic acid In addition, NMR was measured using TMS internal standard substance in DMSO- _d6 , and the values in parentheses in the elemental analysis data are calculated values (%), and the values without parentheses are measured values. (%) shall be shown respectively.

【table】

Claims (1)

[Claims] 1 General formula RO(CH ₂ ) _o S ⁺ R ₁ R ₂・Y ^- [In the formula, R is naphthyl, cycloalkyl, cyclopropylmethyl, tetrahydronaphthyl, indanyl, adamantyl, alkylene-2- tetrahydrofuranyl or alkyl as a substituent,
Indicates a phenyl group that may have at least one selected from alkenyl, alkoxy, acyl, acylamino, halogen, trihalogenomethyl, carboxyl, hydroxyl, amino, nitro, and cyano group. R ₁ and R ₂ are the same or different, and are alkyl, cycloalkyl, alkenyl, phenyl, cyclopropylmethyl, alkylene-2-tetrahydrofuranyl, alkylene-
2-tetrahydropyranyl or an aralkyl group which may have halogen, carboxyl or hydroxyl groups as substituents. n is 2~
The integer 15 and Y represent inorganic acid residues or organic acid residues other than hydrohalic acid. ] A sulfonium compound represented by