JPH0370698B2 - - 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 (). (In the formula, R ₁ and R ₂ are the same or different and represent a lower alkyl group, and R ₃ is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower acyloxy group, a carboxyethylcarbonyloxy group, a benzoyloxy group, an alkoxycarbonyloxy group, or phenoxycarbonyloxy group, _R4 is a hydrogen atom, hydroxyl group, lower alkoxy group, cycloalkyloxy group, phenoxy group, lower acyloxy group, or benzoyloxy group, n is an integer of 1 to 3, and Y is an acid 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 Examples include -butyl, pentyl, hexyl, and the like. In the general formula (), 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. The lower acyloxy group represented by R ₄ is an acyloxy group having 2 to 6 carbon atoms, such as acetyloxy, propionyloxy, butyryloxy, pivaloyloxy, cabroyloxy group, etc., and the alkoxycarbonyloxy group represented by R ₃ is an acyloxy group having a carbon number of 2 to 6 carbon atoms. 2 to 5 alkoxycarbonyloxy groups, such as methoxycarbonyloxy, ethoxycarbonyloxy, propyloxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, t
Examples of the -butoxycarbonyloxy group and the cycloalkyloxy group represented by _R4 include cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy groups. In the general formula (), the acid residue represented by Y may be any one that can be 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 (In the formula, R ₁ , R ₃ , R ₄ and n have the same meanings as above.) A sulfide compound represented by the general formula R ₂ Y ... () (In the formula, R ₂ and Y have the same meanings as above) ) to react with the compounds shown in the table. 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. Compound R ₂ Y may be used in an excess amount relative to the sulfide compound (), but preferably 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,
Other acetone, petroleum ether, ethyl acetate,
Water and mixed solvents of these solvents can be used. The reaction can be carried out in a sealed container if necessary. The sulfide compound represented by the general formula () used as a raw material is, for example, the general formula R ₁ S (CH ₂ ) nCO-hal ... () (wherein R ₁ and n have the same meanings as above, hal
indicates a halogen atom. ) and a compound represented by
general formula (In the formula, R ₃ and R ₄ have the same meanings as above.) The compound represented by is 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 these carbonates or pyridine, morpholine, piperidine, piperazine, triethylamine, etc., at a temperature of about 0 to 200° C. without a solvent or in a suitable 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 ... () (Formula Z in the middle is a silver atom or an alkali metal atom and Y ₁
represents an acid residue other than the halogen atom represented by X. ) 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 ()
However, it is preferably used in an amount of about 1 to 4 times the logical 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 ... () (wherein Y ₁ is the same 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 a free form that can provide an acid residue represented by compound Y 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. The compound of the present invention not only has an anti-allergic effect, but also has an effect of enhancing the immune function of the living body; an anti-cancer effect;
Immunomodulatory effect; anti-inflammatory analgesic effect; liver function improvement effect;
Anti-autoimmune effect; infection prevention effect; side effect prevention of active ingredient compounds such as steroids and anticancer drugs that have immunosuppressive effects as side effects; auxiliary effect for immunotherapy; platelet aggregation inhibiting effect; biological growth regulating effect, etc. It is useful as a medicine and agrochemical. When the compound of the present invention is used as a medicine, various dosage forms can be adopted depending on the therapeutic purpose. Examples of such forms include oral preparations, injection preparations, rectal suppositories, and inhalation preparations, and these dosage forms can be manufactured 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, Tablets, coated tablets, granules, powders, capsules, etc. can be produced by this method. 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 preparations. Desirably, the amount is about 0.1 to 500 mg for injections, about 5 to 1000 mg for suppositories, and about 1 to 500 mg for inhalers. 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 4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoylmethylmethyl sulfide 2.00 g of triethylamine and 2.11 g of 4-(3-ethoxy-2-hydroxypropoxy)aniline were added to 4 ml of dimethylformamide. dissolve. Add methyl mercaptoacetyl chloride to this under ice cooling.
Add 1.25g. After stirring 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, it is concentrated. The residue was purified by column chromatography (silica gel, ethanol:chloroform = 1:5) to obtain 2.85 g of 4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoylmethylsulfide (yield
95.3%). NMR (DMSO−d ₆ , δ value, ppm) 1.15 (3H, O ₂ CH ₃ BECH ₂ O−), 2.19 (3H,
CH ₃ S−) 3.33 (2H, −SCH ₂ −), 3.9−4.3 (3H,

【formula】, 6.89, 7.46 (4H,

[Formula], 8.30 (1H, CONH) Reference Example 2 Synthesis of 2-{4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl}ethylmethylsulfide Add triethylamine to 4 ml of dimethylformamide
1.46 g and 1.52 g of 4-(3-ethoxy-2-hydroxypropoxy)aniline are dissolved. Add 1.10 g of 3-methylmercaptopropionyl chloride to this under ice cooling. After stirring at room temperature for 12 hours, the reaction solution was concentrated and the residue was extracted with chloroform. The chloroform layer is washed with 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and then water, and then concentrated. Ether was added to the residue, the precipitated crystals were collected, and 2-
1.52 g (yield 67.4%) of {4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl}ethylmethylsulfide is obtained. mp79−81
°C Example 1 Synthesis of 4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoylmethyldimethylsulfonium p-toluenesulfonate (compound 1) 4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoylmethylsulfonate Eyed
After dissolving 2.99 g in 20 ml of methylene chloride, 5.50 g of methyl p-toluenesulfonate was added thereto, and the mixture was stirred at room temperature for 24 hours. Ether was added to the reaction solution to remove the insoluble portion, which was recrystallized from methylene chloride-ether to give 4-(3-ethoxy-2
-Hydroxypropoxy)phenylcarbamoylmethyldimethylsulfonium p-toluenesulfonate (Compound 1) 4.75g (yield 97.7%) is obtained. mp139-141°C Example 2 Compounds 8, 12, 16, 27, 28, 32 and 34 shown in Table 1 below were synthesized in the same manner as in Example 1. Example 3 Synthesis of 4-(2-acetoxy-3-ethoxypropoxy)phenylcarbamoylmethyldimethylsulfonium p-toluenesulfonate (compound 2) 4-(2-acetoxy-3-ethoxypropoxy)phenylcarbamoylmethylsulfide
Add 7 g of methyl p-toluenesulfonate to 3.41 g and stir at room temperature for 8 hours. Ether was added to the reaction solution, the insoluble portion was removed, and recrystallized from ethanol ether to give 5.10 g of 4-(2-acetoxy-3-ethoxypropoxy)phenylcarbamoylmethyldimethylsulfonium p-toluenesulfonate (Compound 2) ( Yield: 96.6%). mp100-105°C Example 4 Compounds 5, 6, 17, 18, 19, 21, 22, 25, 26, 29 and 33 shown in Table 1 below were synthesized by the same operation as in Example 3. Example 5 Synthesis of 2-{4-(2,3-dihydroxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium iodide (compound 3) 2-{4-(2,3-dihydroxypropoxy)phenylcarbamoyl}ethyl Dissolve 2.85 g of methyl sulfide in 5 ml of dimethylformamide. Add 5.00g of methyl iodide to this,
Stir at room temperature for 12 hours. Add ether to the reaction solution, remove the insoluble part, recrystallize from methanol-ether, and obtain 2-{4-(2,3-dihydroxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium iodide (compound 3).
Obtain 4.05 g (94.8% yield). mp113-115°C Example 6 Compounds 9, 13, 35 and 37 shown in Table 1 below were synthesized by the same operation as in Example 5. Example 7 Synthesis of 2-{4-(2,3-dihydroxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium p-toluenesulfonate (compound 4) 2-{4-(2,3- Dihydroxypropoxy) phenylcarbamoyl}ethyldimethylsulfonium iodide 2.85g
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, the residue was purified with methylene chloride-ether, and 2-{4-
(2,3-dihydroxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium p-
Toluenesulfonate (compound 4) 4.11g (yield
96.3%). Example 8 Compounds 10, 36 and 38 shown in Table 1 below were synthesized in the same manner as in Example 7. Example 9 Synthesis of 2-{4-(3-butoxy-2-hydroxypropoxy)phenylcarbamoyl)ethyldimethylsulfonium p-toluenesulfonate (compound 14) 2-{4-(3-butoxy) synthesized in Example 6 −
4.83 g of 2-hydroxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium iodide is dissolved in 20 ml of methanol, 2.31 g of silver oxide is added thereto, and the mixture is stirred at room temperature for 1 hour and then filtered. A solution of 3.44 g of p-toluenesulfonic acid in 5 ml of methanol is added to the solution, and then concentrated. The residue was purified with acetonitrile-ether,
2-{4-(3-butoxy-2-hydroxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium p-toluenesulfonate (compound
14) Obtain 5.10g (yield 96.6%). Example 10 Synthesis of 2-{4-(2-hydroxy-3-propoxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium picrylsulfonate (compound 11) 2-{4(2-hydroxy-3) synthesized in Example 6 -Propoxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium 4.69 g of iodide is dissolved in 5 ml of water, a solution of 6 g of sodium picrylsulfonate dissolved in 10 ml of water is added thereto, the precipitated crystals are collected, and 2-{ 4-(2-hydroxy-3-propoxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium
Picryl sulfonate (compound part 11) 6.11g (yield
96.2%). mp117-119℃ Example 11 Synthesis of 2-{4-(3-butoxy-2-hydroxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium picrylsulfonate (compound 15) 2-{4-( 3-butoxy-
Dissolve 5.28 g of 2-hydroxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium p-toluenesulfonate in 5 ml of water, and add a solution of 9 g of sodium picrylsulfonate in 10 ml of water. The precipitated crystals were collected and recrystallized from ethanol to give 2-{4-(3-butoxy-2-
6.50 g (yield 93.5%) of hydroxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium picrylsulfonate (compound 15) is obtained. mp106-108℃ Example 12 Synthesis of 2-{4-(2-hydroxy-3-methoxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium p-toluenesulfonate (compound 7) 2-{4-(2-hydroxy-3 -Methoxypropoxy)phenylcarbamoyl}To a solution of 2.99 g of ethyl methyl sulfide in 30 ml of methylene chloride, 4.00 g of methyl iodide and then 2.79 g of silver p-toluenesulfonate are added, and the mixture is stirred at room temperature for 12 hours. The reaction solution is filtered, and hydrogen sulfide and activated carbon are added to the solution. The liquid was concentrated and recrystallized from ethanol-ether to give 2-{4-(2-
Hydroxy-3-methoxypropoxy) phenylcarbamoyl}ethyldimethylsulfonium
p-Toluenesulfonate (compound 7) 4.71g
(yield 96.9%). mp144-146℃ Example 13 Compounds shown in Table 1 below in the same manner as Example 12
20, 23, 30, 31, 33 and 39 were synthesized. Example 14 2-{3-(2-phenoxycarbonyloxy-
Synthesis of 3-ethoxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium p-toluenesulfonate (compound 24) 2-{3-(2-phenoxycarbonyloxy-
Dissolve 4.34 g of 3-ethoxypropoxy)phenylcarbamoyl}ethylmethylsulfide in 10 ml of acetonitrile, add 5.00 g of propyl iodide, and then add 2.79 g of silver p-toluenesulfonate.
g and stirred at room temperature for 12 hours. After the reaction solution was filtered, it was treated in the same manner as in Example 12 to give 2-{3-(2
-Phenoxycarbonyloxy-3-ethoxypropoxy)phenylcarbamoyl}ethyldimethylsulfonium p-toluenesulfonate (Compound 24) 6.05g (yield 93.4%) was obtained. Compounds obtained in each of the above Examples (Compounds 1 to 1)
39) 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.

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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, and R ₃ is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower acyloxy group, a carboxyethylcarbonyloxy group, a benzoyloxy group, an alkoxycarbonyloxy group, or phenoxycarbonyloxy group, _R4 is a hydrogen atom, hydroxyl group, lower alkoxy group, cycloalkyloxy group, phenoxy group, lower acyloxy group, or benzoyloxy group, n is an integer of 1 to 3, and Y is an acid A sulfonium compound represented by (the residues are shown respectively).