JPH0370699B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel sulfonium derivatives. The sulfonium derivative of the present invention is represented by the following general formula (). (In the formula, R ₁ and R ₂ are the same or different and represent a lower alkyl group, R ₃ is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower acyloxy group, or a benzoyloxy group, and R ₄ is a hydrogen atom, a hydroxyl group, a lower alkoxy group) group, lower alkoxy-substituted ethoxy group, tetrahydrofurfuryloxy group, tetrahydropyranylmethyloxy group, phenoxy group, carbamoyloxy group, lower acyloxy group or benzoyloxy group, n is an integer of 2 or 3, and Y is 3
Each acid residue is indicated. ) In the above general formula (), the lower alkyl group represented by R ₁ and R ₂ is an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, The lower alkoxy group represented by R ₃ and R ₄ includes an alkoxy group having 1 _to 6 carbon atoms, such as methoxy, ethoxy, propyloxy, isopropyloxy, butoxy, hexyloxy group, etc. Examples of the lower acyloxy group represented by ₄ include acyloxy groups having 2 to 6 carbon atoms, such as acetyloxy, propionyloxy, butyryloxy, pivaloyloxy, and caproyloxy groups. The lower alkoxy group which is a substituent in the lower alkoxy-substituted ethoxy group represented by R ₄ also has the same meaning as shown above. In addition, the acid residue represented by Y in the general formula () may be any one used as a pharmaceutical,
Specifically, the following inorganic acid residues and organic acid residues can be exemplified. Inorganic acid residues: acid residues such as hydrogen chloride, hydrogen iodide, hydrogen bromide, tetrafluoroboric acid, perchloric acid, phosphoric acid, etc. Organic acid residues: organic sulfonic acid residues such as methanesulfonic acid, toluenesulfonic acid, camphorsulfonic acid, and 1,5-naphthalenedisulfonic acid, and carboxylic acid residues such as lactic acid, maleic acid, and malonic acid. The sulfonium compound of the present invention represented by the above general formula () has antiallergic effects and is useful as a pharmaceutical. The method for producing the compound of the present invention will be explained below. The compounds of the present invention can be produced, for example, by the following various methods. [Manufacturing method A] General formula (wherein R ₁ , R ₃ , R ₄ and n have the same meanings as above) and the general formula R ₂ Y () (wherein R ₂ and Y have the same meanings as above) ) is reacted 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.
Examples of 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 mixed solvents of these solvents can be used. The reaction can be carried out in a closed container if necessary. The sulfide compound represented by the general formula () used as a raw material in the above is, for example, the general formula R ₁ S (CH ₂ ) _o -hal () (wherein R ₁ and n have the same meanings as above, hal
represents a halogen atom) and the general formula (In the formula, R ₃ and R ₄ have the same meanings as above.) Preferably, a basic compound, such as an alkali metal such as sodium or potassium, a hydride thereof, or a hydroxide thereof. Alternatively, it can be synthesized by reaction in the presence of carbonates thereof, pyridine, morpholine, piperidine, piperazine, triethylamine, etc., at a temperature of about 0 to 200° C. without a solvent or in an appropriate solvent. Details of the synthesis of the sulfide compound of the general formula () are as follows:
This will be described in the reference example below. [Manufacturing method B] General formula (In the formula, R ₁ , R ₂ , R ₃ , R ₄ and n have the same meanings as above, and X represents a halogen atom.) and the general formula ZY ₁ () (in the formula, Z is a silver atom or an alkali metal atom and Y ₁
represents an acid residue other than the halogen atom represented by Z. ) is reacted with the compound represented by This method utilizes a salt exchange reaction of a sulfonium halide represented by the general formula () (in the compound represented by the general formula () of the present invention, Y represents a hydrohalic acid residue), and The raw material compound is produced according to Production Method A above. The sulfonium halide (2) can be advantageously used in the present reaction in the form of a reaction mixture without being isolated from the reaction system. Of course, it can also be used after being isolated and purified from the reaction system. As the compound represented by the general formula (), silver salts or alkali metal salts of acids capable of providing the acid residue corresponding to Y in the general formula () of the present invention can be used. Examples of the above acids include hydrogen chloride, hydrogen bromide,
Inorganic acids such as hydrogen iodide, perchloric acid, tetrafluoroboric acid, maleic acid, malonic acid, lactic acid, camphorsulfonic acid, methanesulfonic acid, tosylic acid, picrylsulfonic acid, 1,5-naphthalenedisulfonic acid For example, organic acids such as Examples of the alkali metals include sodium, potassium, and lithium. This salt exchange reaction is carried out in a solvent at about -30 to 150°C, preferably about 0 to 100°C. The compound represented by the general formula () is a sulfonium halide ()
It is preferably used in an amount of about 1 to 4 times the theoretical amount. As the solvent, any of the same various solvents used in the reaction of production method A above can be used. [Production method C] This method also utilizes a salt exchange reaction, in which the sulfonium halide represented by the above general formula () is combined with silver oxide and the general formula HY ₁ () (where Y ₁ has the same meaning as above). ) is reacted with the compound represented by The sulfonium halide used as a raw material is the same as that shown in production method B, and
The compound represented by HY ₁ is an organic or inorganic acid in free form that can provide the acid residue represented by Y in the compound represented by the general formula () of the present invention. A specific example thereof is as shown in the manufacturing method B above. In this reaction, silver oxide can be used in a molar ratio of usually at least equimolar, preferably about 1 to 4 times, relative to the sulfonium halide () used as a raw material. Also
The proportion of the acid represented by HY ₁ to be used is preferably at least equimolar, preferably about 1 to 4 times the molar ratio of the sulfonium halide () used as the raw material. This reaction is usually carried out in a solvent at about -30 to 150°C, preferably about 0 to 100°C. The solvent may be the same as that used in Production Method A above. The sulfonium compound of the present invention obtained according to the above production methods A to C can be isolated according to a conventional separation method after the reaction is completed. As the separation method, for example, a recrystallization method, an extraction method, a concentration method, a column chromatography, etc. can be adopted. In addition to having anti-allergic effects, the compounds of the present invention also have anti-allergic effects; enhance immune function of the living body; anti-cancer effects; immunoregulatory effects; anti-inflammatory and analgesic effects; liver function-improving effects; anti-autoimmune effects; infection-protecting effects; side effects. Compounds that have immunosuppressive effects as side effects of active ingredient compounds such as steroids and anticancer drugs; auxiliary action for immunotherapy; platelet aggregation inhibiting action;
It has biological growth regulating effects and is useful as medicines and agricultural chemicals. When the compound of the present invention is used as a medicine, various dosage forms can be adopted depending on the therapeutic purpose. The dosage form may be, for example, an oral preparation, an injection, a rectal suppository, an inhalation, etc., and each of these dosage forms can be manufactured by a conventional formulation method 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, an adhesive, 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, add a PH adjusting agent, a buffer, a stabilizer, a tonicity agent, a local anesthetic, etc. to the compound of the present invention, and prepare a subcutaneous, intramuscular, or intravenous injection using a conventional method. can be manufactured. When preparing rectal suppositories, the suppositories can be manufactured 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 necessary, and the inhalant can be manufactured by a conventional method. The amount of the compound of the present invention to be incorporated into each of the above dosage unit forms varies depending on the symptoms of the patient to whom it is applied or the dosage form, but generally it is about 5 to 1000 mg per dosage unit form for oral formulations. , about 0.1 to 500 mg for injections, about 5 to 1000 mg for suppositories,
For inhalants, the amount is preferably about 1 to 500 mg. or,
The daily dosage of the drug having the above dosage form cannot be determined unconditionally depending on the symptoms, etc., but it is usually about 0.1
It is preferable to set it as 5000 mg. Next, in order to further explain the present invention, reference examples and examples will be shown. Reference Example 1 Synthesis of 2-{4-(2,3-dihydroxypropoxy)phenoxy}ethylmethylsulfide Sodium hydroxide 0.40g and 90% methanol 10
4-(2,3-dihydroxypropoxy) in ml
After dissolving 1.84 g of phenol, 1.11 g of 2-methylmercaptoethyl chloride was added thereto, and the mixture was refluxed for 6 hours. The reaction solution was concentrated, and the residue was extracted with chloroform. The chloroform layer is washed with water, dehydrated with Glauber's salt, and then concentrated. The residue was recrystallized from benzene-petroleum ether to obtain 2.25 g (yield: 87.2%) of 2-{4-(2,3-dihydroxypropoxy)phenoxy}ethylmethylsulfide. mp59−61°C Elemental analysis C ₁₂ H ₁₈ O ₄ As S Potassium hydroxide 0.56g and 90% ethanol 10ml
2.40 g of 4-(2,3-diethoxypropoxy)phenol was dissolved in the solution, 1.55 g of 2-methylmercaptoethyl bromide was added thereto, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, and the residue was extracted with chloroform. After washing the chloroform layer with water and dehydrating the sodium sulfate,
Concentrate. The residue was distilled under reduced pressure to give 2-{4-(2,
2.95 g (yield 93.9%) of 3-diethoxypropoxy)phenoxy}ethylmethylsulfide is obtained. bp176-177℃/1-2mmHg Example 1 Synthesis of 2-{2-(2,3-dihydroxypropoxy)phenoxy}ethyldimethylsulfonium p-toluenesulfonate (compound 1) 2-{2-(2,3- dihydroxypropoxy) phenoxy}ethyl methyl sulfide 2.58
7 g of methyl p-toluenesulfonate was added to g and 5 ml of methylene chloride, and the mixture was stirred at room temperature for 24 hours. Ether was added to the reaction mixture, the precipitated oil was separated and purified with ethanol-ether to give 2-
4.01 g (yield 91.1%) of {2-(2,3-dihydroxypropoxy)phenoxy}ethyldimethylsulfonium p-toluenesulfonate is obtained. Example 2 Compounds 3, 5, 9, and 15 shown in Table 1 below were synthesized in the same manner as in Example 1. Example 3 Synthesis of 2-{4-(2-hydroxy-3-methoxypropoxy)phenoxy}ethyldimethylsulfonium p-toluenesulfonate (compound 6) 2-{4-(2-hydroxy-3-methoxypropoxy)phenoxy} Add 6 g of methyl p-toluenesulfonate to 2.72 g of ethyl methyl sulfide and stir at room temperature for 12 hours. Ether was added to the reaction solution, the insoluble matter was separated and recrystallized from ethanol-ether to give 2-{4-(2-hydroxy-
3-Methoxypropoxy)phenoxy}ethyldimethylsulfonium, p-toluenesulfonate
Obtain 4.15 g (90.4% yield). mp88-91°C Example 4 Compounds 7, 8, 10, 13, 16 and 17 shown in Table 1 below were synthesized in the same manner as in Example 3. Example 5 Synthesis of 2-{4-(2-hydroxy-3-phenoxypropoxy)phenoxy}ethyldimethylsulfonium iodide (compound 11) 2-{4-(2-hydroxy-3-phenoxypropoxy)phenoxy }Add 5 g of methyl iodide to 3.34 g of ethyl methyl sulfide and 5 ml of acetonitrile, and stir at room temperature for 24 hours. The reaction solution was concentrated, and the residue was recrystallized from ethanol-ether to give 2-{4-(2-hydroxy-3-
phenoxypropoxy) phenoxy}ethyldimethylsulfonium iodide 4.45g (yield
93.5%). mp112-112.8°C Example 6 Compound 20 shown in Table 1 below was synthesized in the same manner as in Example 5. Example 7 3-{4-(3-ethoxy-2-hydroxypropoxy)phenoxy}propyldimethylsulfonium p-toluenesulfonate (compound
21) Synthesis of 3-{4-(3-ethoxy-
2-Hydroxypropoxy)phenoxy}propyldimethylsulfonium iodide 4.42g
was dissolved in 20 ml of acetonitrile, 2.79 g of silver p-toluenesulfonate was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution is filtered, and hydrogen sulfide and activated carbon are added to the solution. The liquid was concentrated and the residue was recrystallized from ethanol-ether to give 3-{4-(3-
4.48 g (yield 92.0%) of ethoxy-2-hydroxypropoxy)phenoxy}propyldimethylsulfonium p-toluenesulfonate is obtained. mp114-116℃ Example 8 2-{4-(2,3-propoxypropoxy)phenoxy}ethyldimethylsulfonium p-
Synthesis of toluenesulfonate (compound 14) 3.42 g of 2-{4-(2,3-propoxypropoxy)phenoxy}ethylmethylsulfide and 5 g of methyl iodide in 20 ml of acetonitrile,
Next, 2.79 g of silver p-toluenesulfonate was added, and the mixture was stirred at room temperature for 12 hours. Filter the reaction solution,
Hydrogen sulfide and activated carbon are added to the solution and filtered. The liquid was concentrated, and the residue was recrystallized from methanol-isopropyl ether to give 4.81 g of 2-{4-(2,3-propoxypropoxy)phenoxy}ethyldimethylsulfonium p-toluenesulfonate.
(yield 90.9%). mp123-125°C Example 9 Compounds 18 and 19 shown in Table 1 below were synthesized in the same manner as in Example 8. Example 10 2-{4-(2-hydroxy-3-phenoxypropoxy)phenoxy}ethyldimethylsulfonium p-toluenesulfonate (compound
Synthesis of 12) 4.76 g of 2-{4-(2-hydroxy-3-phenoxypropoxy)phenoxy}ethyldimethylsulfonium iodide synthesized in Example 5
Dissolve silver in 20ml of acetonitrile and add silver oxide to this.
Add 2.32g and stir for 30 minutes. Filter the reaction solution,
Add 3.44 g of p-toluenesulfonic acid to the liquid and concentrate. The residue was recrystallized from acetonitrile-ether to give 2-{4-(2-hydroxy-3-phenoxypropoxy)phenoxy}ethyldimethylsulfonium p-toluenesulfonate 4.65
g (yield 89.3%). mp88-90℃ Example 11 Synthesis of 2-{2-(2,3-dihydroxypropoxy)phenoxy}ethyldimethylsulfonium picrylsulfonate (compound 2) 2{2-(2,3- dihydroxypropoxy) phenoxy}ethyldimethylsulfonium p-toluenesulfonate 4.45g
was dissolved in 2 ml of water, and to this was added 6.30 g of sodium picrylsulfonate dissolved in 10 ml of water. The precipitated crystals were collected and recrystallized from ethanol to obtain 5.10 g (90.1%) of 2-{2-(2,3-dihydroxypropoxy)phenoxy}ethyldimethylsulfonium picrylsulfonate. mp124-125°C Example 12 Compound 4 shown in Table 1 below was synthesized in the same manner as in Example 11. Example 13 Synthesis of 3-{3-(3-ethoxy-2-propionyloxypropoxy)phenoxy}propylmethylpropylsulfonium p-toluenesulfonate (compound 22) 3-{3-(3-ethoxy-2-propionyloxypropoxy) ) Dissolve 3.56 g of phenoxy}propyl methyl sulfide in 20 ml of methylene chloride, add 5 g of methyl iodide, then add p.
- Add 2.79 g of silver toluenesulfonate and leave at room temperature.
Stir for 24 hours. The reaction solution is filtered, and hydrogen sulfide and activated carbon are added to the solution. The liquid was concentrated and the residue was purified with acetonitrile-isopropyl ether to give 3-{3-(3-ethoxy-2-
4.95 g (91.2%) of propionyloxypropoxy)phenoxy}propylmethylpropylsulfonium p-toluenesulfonate are obtained. Compounds obtained in each of the above Examples (Compounds 1 to 1)
22) structure, yield (%), mp (℃) of each compound, elemental analysis value, and nuclear magnetic resonance spectrum (NMR) analysis result (δ value, ppm) for each example
are shown in Table 1 below. In Table 1, the values shown in parentheses in the elemental analysis values are calculated values (%), and the values shown without parentheses are actually measured values (%).
shall be shown. In addition, NMR in DMSO−d ₆
This is a value measured using TMS as an internal standard substance.

【table】

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ and R ₂ are the same or different and represent a lower alkyl group, R ₃ is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower acyloxy group, or a benzoyloxy group, and R ₄ is a hydrogen atom, a hydroxyl group, a lower alkoxy group) group, lower alkoxy-substituted ethoxy group, tetrahydrofurfuryloxy group, tetrahydropyranylmethyloxy group, phenoxy group, carbamoyloxy group, lower acyloxy group or benzoyloxy group, n is an integer of 2 or 3, and Y sulfonium derivatives represented by (indicate acid residues).