JPS642087B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to antitumor agents. The antitumor agent of the present invention is characterized in that it contains a sulfonium compound represented by the following general formula () as an active ingredient. In the formula, R ₁ , R ₂ and R ₃ are the same or different and represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an acyl group and an amino group, and A represents the general formula
A linear or branched alkylene group represented by CnH _2o (n is an integer of 2 to 5), and Y means an inorganic acid residue or an organic acid residue. The halogen atoms represented by R ₁ , R ₂ and R ₃ in the above general formula () include chlorine, fluorine, bromine,
Iodine, the alkyl group is a branched or straight-chain lower alkyl group such as methyl, ethyl, n-propyl, isopropyl group, etc., the alkoxy group is a lower alkoxy group such as methoxy, ethoxy, etc., and the acyl group is can be exemplified by lower alkylcarbonyl groups such as acetyl and butyryl. Preferred examples of the linear or branched alkylene group having 2 to 5 carbon atoms represented by A in the general formula () include ethylene, triethylene, propylene, tetraethylene, and pentaethylene. The inorganic acid residues and organic acid residues represented by Y are preferably halogens such as chlorine, fluorine, bromine, and iodine, inorganic acid residues such as perchlorate and tetrafluoroborate, and cyclohexylsulfamate, p- Examples include organic acid residues such as toluenesulfonate. The present inventors discovered for the first time that a group of sulfonium compounds represented by the above general formula () have an antitumor effect, as detailed in the pharmacological test examples described below, and based on this knowledge, the present invention was developed. completed. The sulfonium compounds represented by the above general formula () include some known compounds, but it is of course completely unknown that these compounds have antitumor effects. Each compound represented by the above general formula () used as an active ingredient of the antitumor agent of the present invention can be produced, for example, by Method A and Method B below. <Method A> General formula (wherein R ₁ , R ₂ , R ₃ and A have the same meanings as above) and a compound represented by the general formula CH ₃ Y () (wherein Y has the same meanings as above) React with the compound represented by The compounds represented by the general formula () and the general formula () are known. This reaction is carried out without a solvent or in a solvent at about -20 to 150°C, preferably about 0 to 100°C, and the compound of general formula () is used in a molar amount of 1 to 4 times that of the compound of general formula (). is preferable. A wide range of solvents can be used as long as they do not participate in the reaction, such as alcohols such as methanol and ethanol, aprotic polar solvents such as acetonitrile, nitromethane, dimethylformamide, and dimethyl sulfoxide, methylene chloride, chloroform, etc. Halogenated hydrocarbons, aromatic hydrocarbons such as benzene and toluene, ethyl ether, propyl ethers, acetone, ethyl acetate, etc. are used. <Method B> General formula (In the formula, X represents halogen, R ₁ , R ₂ , R ₃ and A
has the same meaning as above) and a silver salt represented by the general formula Y ₁ Ag () (wherein Y1 means an inorganic acid residue or an organic acid residue different from X). react. The compounds represented by the general formula () and the compounds represented by the general formula () are known. This reaction is carried out in a solvent at about 0 to 100°C, and the general formula ()
It is preferable to use the compound of general formula () in an amount of about 1 to 4 times the mole of the sulfonium halide.
As the solvent, the same solvent as in <Method A> can be used. The sulfonium compounds obtained according to the above two methods can be easily isolated by conventional isolation methods such as recrystallization and column chromatography. The administration form of the antitumor agent of the present invention is not particularly limited, and may be any of the commonly used forms such as oral preparations, injections, and rectal suppositories, and can be manufactured by conventional formulation methods known to those skilled in the art. When preparing a solid preparation for oral use, the sulfonium compound represented by the above general formula () is used as an active ingredient, and excipients are added to this, and if necessary, binders, disintegrants, lubricants, colorants, After adding a flavoring agent, flavoring agent, etc., tablets, coated tablets, granules, powders, capsules, etc. can be prepared by conventional methods. When preparing oral liquid preparations, oral liquid preparations, syrups, dry syrups, etc. can be prepared by adding flavoring agents, buffering agents, stabilizers, flavoring agents, etc. to the active ingredient compound and using conventional methods. When preparing injections, add PH regulators, buffers, stabilizers, isotonic agents, local anesthetics, etc. to the active ingredient compound, and prepare subcutaneous, intramuscular, or intravenous injections using conventional methods. can be manufactured. When preparing a rectal suppository formulation, the suppository can be manufactured by a conventional method after adding excipients and, if necessary, a surfactant and the like to the active ingredient compound. The amount of the active ingredient compound to be incorporated into the above dosage unit form varies depending on the symptoms or dosage form, but is generally about 5 to 1000 mg for oral preparations.
Approximately 0.1 to 100 mg for injections, approximately 0.5 to 500 mg for suppositories
It is desirable to do so. The daily dosage cannot be determined unconditionally depending on the symptoms, etc., but it is usually about 0.1 for adults.
It is preferable to set it as 5000 mg. Next, production examples, formulation examples, antitumor effect test results, and acute toxicity test results of the active ingredient compound of the present invention will be shown. Example 1 Synthesis of 2-benzoyloxyethyldimethylsulfonium p-toluenesulfonate (compound 1) 2-benzoyloxyethylmethylsulfonate
Methyl p-toluenesulfonate 3.72 in 1.96g
After stirring at room temperature for 12 hours, ether is added to the reaction. The precipitated crystals are collected and recrystallized from ethanol-ether to obtain 3.72 g (yield 97.4%) of 2-benzoyloxyethyldimethylsulfonium p-toluenesulfonate. mp. 128-129℃ Elemental analysis value C ₁₈ H ₂₂ S ₂ O ₅ C H Calculated value (%) 56.52 5.80 Actual value (%) 56.31 5.80 Example 2 The following procedure was carried out in the same manner as in Example 1. Compounds 4, 8, 9, 10, 11, 12, 13, 14, 15 shown in the table,
16, 17 and 18 were synthesized. Example 3 Synthesis of 2-(2-methylbenzoyloxy)ethyldimethylsulfonium p-toluenesulfonate (compound 5) Dissolve 3.52 g of 2-(2-methylbenzoyloxy)ethyldimethylsulfonium iodide in 50 ml of dichloromethane, - Add 5.58 g of silver toluenesulfonate and stir at room temperature for 4 hours. The reaction solution is filtered, and after the filtrate is saturated with hydrogen sulfide gas, activated carbon is added and filtered. The filtrate was concentrated, and the residue was recrystallized from ethanol-ether to produce 3.88 g of 2-(2-methylbenzoyloxy)ethyldimethylsulfonium p-toluenesulfonate (yield 97.7).
%). mp. 98-100℃ Elemental analysis value C ₁ 9H ₂₄ S ₂ O ₅ C H Calculated value (%) 57.55 6.10 Actual value (%) 57.62 6.29 Example 4 The following procedure was carried out in the same manner as in Example 3. Compounds 6 and 7 shown in the table were synthesized. Example 5 Synthesis of 2-benzoyloxyethyldimethylsulfonium chloride (compound 2) 3.38g of 2-benzoyloxyethyldimethylsulfonium iodide was dissolved in 50ml of dichloromethane, 2.86g of silver chloride was added thereto, stirred at room temperature for 10 hours, and then filtered. do. Saturate the filtrate with hydrogen sulfide gas, add activated carbon, and filter. Concentrate the liquid and recrystallize the residue from ethanol to obtain 2.35 g of 2-benzoyloxyethyldimethylsulfonium chloride.
(yield 95.1%). mp. 154-156℃ Elemental analysis value C ₁₁ H ₁₅ SO ₂ As Cl C H Calculated value (%) 53.54 6.13 Actual value (%) 53.44 6.10 Example 6 2-benzoyloxyethyldimethylsulfonium cyclohexylsulfamate (compound Synthesis of 3) Dissolve 3.38 g of 2-benzoyloxyethyldimethylsulfonium iodide in 100 ml of ethanol, add 4.29 g of silver cyclohexylsulfamate, and stir overnight at room temperature. The reaction mixture is filtered, the filtrate is saturated with hydrogen sulfide gas, activated carbon is added, and the mixture is filtered. The filtrate is concentrated, and the residue is recrystallized from ethanol-ether to obtain 3.8 g of 2-benzoyloxyethyldimethylsulfonium cyclohexylsulfamate (yield: 97.7%). mp. 120-122℃ Elemental analysis value C ₁₇ H ₂₇ S ₂ O ₅ N Calculated value (%) 52.42 6.99 3.60 Actual value (%) 52.15 7.26 3.63 Compounds obtained in each of the above examples (Compound No. .1～
Table 1 shows the structure, yield (%), mp (°C), and elemental analysis value or NMR analysis value (δ, ppm) of 18). In the elemental analysis values in Table 1, numerical values shown in parentheses indicate calculated values (%), and numerical values shown without parentheses indicate measured values (%). Also
NMR is a value measured using TMS in DMSO- _d6 as an internal standard.

【table】

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ , R ₂ and R ₃ are the same or different and represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an acyl group and an amino group, and A is a general formula
A sulfonium compound represented by a linear or branched alkylene group represented by CnH _2o (n represents an integer of 2 to 5, and Y represents an inorganic acid residue or an organic acid residue). An antitumor agent characterized by containing.