JPS6037114B2 - Thioxanthene derivative - Google Patents

Description

Detailed Description of the Invention The present invention has a central nervous system depressing effect such as a strong locomotor activity suppressing effect, an anti-apomorphine effect, and a conditioned avoidance response suppressing effect, and also has a long-lasting effect. The present invention relates to a novel thioxanthene derivative represented by the general formula and a salt thereof useful as an antipsychotic.

In the above formula, each symbol is as follows.

X represents halogen (fluorine, chlorine, bromine, iodine, preferably fluorine or chlorine), and Y represents hydrogen.

The dotted line of ring A indicates that this part forms a double bond.・Z represents a group of the formula (ie, ring A is a cyclohexane pseudo-cyclohexane ring or a cyclohexane ring).

Here, RI represents halogen (fluorine, chlorine, bromine, iodine, etc., preferably fluorine, chlorine, bromine), R2
represents trifluoromethyl, and R3 represents halogen. The compound of general formula (1) is produced by the following method.

Method 1 [In the formula, T represents a reactive ester group, and examples include halogen atoms such as chlor, bromo, and iodine, and organic sulfonyloxy such as methylsulfonyloxy and /latluenesulfonyloxy, but preferably chloro , bromo, methylsulfonyloxy, para-toluenesulfonyloxy.

Other symbols are the same as above. ] The above reaction scheme may be carried out in the presence or absence of a suitable inert diluent, but it is preferable to use a diluent.

As a diluent, alcohol solvents such as methyl alcohol and ethyl alcohol, ketone solvents such as acetone and methyl ethyl ketone, ether solvents such as tetrahydrofuran and dioxane, halogenated hydrocarbon solvents such as methylene chloride and chloroform, benzene, toluene, Aromatic hydrocarbon solvents such as xylene, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide,
Non-brotic polar solvents such as N-methylpyrrolidone may be used. Furthermore, in order to facilitate the reaction, it is preferable to use a suitable deoxidizing agent to remove the generated acid.
As the deoxidizing agent, either an inorganic base or an organic base can be used. As the inorganic base, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. are used. As organic bases, alkali metal alkoxides such as sodium methylate, sodium ethylate, sodium mutatributyrate, sodium acetate, potassium acetate, triethylamine, pyridine, etc. are used. The reaction temperature is from 10 to 200 degrees Celsius, and if no diluent is used, the reaction temperature is generally from 100 to 200 degrees Celsius. The reaction time is
It varies depending on the diluent used and reaction temperature, but 30 to 7
It's childhood time. Method 2 This method is applied to the production method when Z in general formula (1) represents a group of the formula.

[In the formula, V represents halogen, preferably fluorine, chlorine, or bromine.

Other symbols have the same meanings as above. ] In the method according to the above reaction formula, the oxime formation in step 1 is carried out in the presence of various suitable diluents in a conventional manner.

The reduction reaction in step 2 can be carried out through contact or chemical reduction. As a catalyst for catalytic reduction, a metal such as palladium, platinum, rhodium, nickel/ruthenium, or cobalt, to which an inert carrier such as activated carbon, alumina, barium sulfate, potassium carbonate, or strontium carbonate is attached, is used. The reaction time depends on hydrogen pressure, reaction temperature, etc., and generally takes a long time at atmospheric pressure and room temperature.
Metal hydride compounds are conveniently used for chemical reduction. This reduction includes lithium aluminum hydride, lithium borohydride, sodium borohydride, dihydrobis(2-
methoxyethoxy) sodium aluminate, etc. are used. The condensation of step 3 can be carried out in a diluent at elevated reaction temperatures. Ethyl alcohol, n-butyl alcohol, n-amyl alcohol as a diluent,
Isoamyl alcohol, ethylene glycol, methyl alcohol.

Solv, ethyl cellosolve, cyclobentanol, cyclohexanol, alcohol diluents such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, ether solvents such as diethylene glycol dimethyl ether, dimethyl formamide,
Aprotic polar diluents such as dimethyl sulfoxide, dimethyl sulfone, N-methylpyrrolidone, and hexamethylphosphoramide are used. Furthermore, in order to facilitate the reaction, a suitable inorganic base,
Organic bases are used. Further, potassium iodide or the like is used as a reaction accelerator catalyst. Representative bases include sodium carbonate, potassium carbonate, lithium carbonate, sodium acetate, and potassium acetate. The reduction reaction in step 4 can be carried out by either catalytic reduction or chemical reduction, but when a double bond exists in far A of the formula (wind) or when RI represents a halogen, it is preferably carried out by catalytic reduction or chemical reduction. Chemical reduction is preferred. Chemical reduction can be carried out using metals or metal compounds, such as zinc dust, stannous chloride, etc., in catalysts that may be acidic, neutral or alkaline. The cyclization reaction in step 5 uses phosgene, alkali metal cyanate (potassium cyanate, sodium cyanate, etc.), urea, urethane, trichlorponyldimidazole, etc. as a cyclization agent, and the presence of an appropriate diluent. The melting reaction can be carried out under or without a melting reaction. When phosgene or carbonyldimidazole is used, the reaction proceeds sufficiently at about 5° C. to room temperature, but when alkali metal cyanate is used, the reaction proceeds at a temperature of 80 to 150°. When urea, urethane, etc. are used, the reaction can proceed in a molten state. Method 3 This method is lightly applied to the production method when Z in general formula (1) represents a group of the formula.

[Wherein, M represents an alkali metal (lithium, potassium, sodium, calcium, etc.), preferably potassium or sodium. Other symbols are the same as above. ] In the method of the above reaction formula, step 1 is generally applied to the production of aminonitrile.

Solvents used include water, water-soluble solvents such as acetic acid, methanol, ethanol, and propanol, water-soluble ether solvents such as tetrahydrofuran and dioxane, and aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide. mixed solvent (e.g. water-
(acetic acid), but water, acetic acid, methanol, and other water-based solvents are preferred. Potassium cyanide and sodium cyanide are suitable as MCN (cyanide compound). The reaction temperature and reaction time vary depending on the individual reaction, but generally 0 to 100 oo and 1 to 4 hours are appropriate.
When the hydrolysis in step 2 is generally carried out under acidic conditions, hydrochloric acid,
Hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc. are used, and under basic conditions, alkali hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc. are used, but sulfuric acid is preferably used. , hydrochloric acid, potassium hydroxide, sodium hydroxide, etc. The solvent used is water, methanol,
Alcohol solvents such as ethanol, propanol, and ethylene glycol; aliphatic carboxylic acid solvents such as acetic acid, propionic acid, and trifluoroacetic acid; ether-based aqueous solvents such as tetrahydrofuran and dioxane; dimethylformamide and dimethyl sulfoxide. Examples include aprotic polar solvents such as

Although the reaction temperature and reaction time vary depending on the individual reaction, generally 0 to 150 degrees Celsius and 0 minutes to 24 hours are appropriate. Examples of the condensing agent and solvent in the cyclization reaction in Step 3 include formamide, an aqueous formaldehyde solution, and paraformaldehyde, and formamide and an aqueous formaldehyde solution are preferred.

Note that formic acid or concentrated sulfuric acid may be used as an acid catalyst to promote the reaction. The reaction temperature and reaction time vary depending on the individual reaction, but 100 to 250°C and 1 to 4 gluing times are suitable. Method 4 This method is applied to the production method when Z in general formula (1) represents a group of the formula.

[In the formula, Hal represents bromine or chlorine.

Other symbols have the same meanings as above. ] The method of the above reaction formula is carried out in a solvent such as an ether solvent such as ether, tetrahydrofuran or dioxane, or an aromatic hydrocarbon solvent such as benzene, toluene or xylene.

In the latter case, tertiary amines such as dimethylaniline, diethylaniline, pyridine are used as additives. Ether and tetrahydrofuran are preferred. Reaction temperature and reaction time vary depending on the individual reaction, but -30 to 15
0oo, 0.5 to 1 feeding time is appropriate. General formula (1)
In the compound, when ring A is a cyclohexeso ring, an asymmetric carbon occurs and an inactive racemate is obtained. This racemate can usually be resolved into optically active forms by well-known methods. The base of general formula (1) produced by the above method can be made into pharmaceutically acceptable acid addition salts and quaternary salts.

The acid for forming the salt is appropriately selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as maleic acid, fumaric acid, succinic acid, citric acid, and alcoholic acid. I can do it. Examples of the quaternary chlorinating agent include dimethyl sulfate, diethyl sulfate, methyl iodide, and ethyl furomide. The present invention will be specifically explained below using Examples.

Example 12'-chloro-4-mesyloxyspiro [
Cyclohexane-1,9' monothioxanthene] 7.9g
, 5-chloro-1-(4-piveridyl)-121-benzimidazolinone5. Female, potassium carbonate 2. Definitely potassium iodide 3. male, a mixture of 50 parts dimethylformamide and 6 parts
It flies for 9 feeding hours at 5q0.

After cooling the reaction solution to room temperature, it is poured into ice water. The precipitated solid substance is dissolved in chloroform, washed with water, dried, and then the solvent is distilled off. Afterglow was removed by column chromatography [using silica gel: developing solvent: chloroform-methanol (9:1)]
] to separate and purify. When the obtained target base is converted into a hydrochloride salt using a conventional method, white crystals with a melting point of 293°C (decomposition) are obtained.
2-chloro-4-[4-(5-chloro)-2-oxo-
1-penzimidazolinyl)biveridino]-spiro[cyclohexane-1,9'-monothioxanthene] hydrochloride is obtained. Novel 2'-chloro4 used as raw material
-Mesyloxyspiro [cyclohexane 1,9' monothioxanthene] is prepared by the following method.

2'1 Chlorospiro [2-shiku.

Dissolve 1 female of hexene-1,9'monothioxanthene]-4-one in 200 g of glacial acetic acid and add 3 g of 10% palladium on carbon.
was added, and hydrogen gas was introduced into this at an internal temperature of 6000 for 6 hours. Furthermore, a palladium carbon disk was added and hydrogen gas was introduced for 6 hours. After the reaction is complete, the palladium on carbon is removed from the furnace, water is added, the mixture is made alkaline with potassium carbon, and then extracted with chloroform. After washing the extract with water and drying, chloroform is distilled off. The remaining oil is treated with ethanol to crystallize it, and the crude crystals are recrystallized from ethanol.
2'-chlorospiro[cyclohexane-1,9'-1thioxanthene]-14-one having a melting point of 111-11,300 is obtained. 2'-chlorospiro [cyclohexane-1
,9'monothioxaneteso]14-one32. Suspend the peak in 300 ml of ethanol and add 3 ml of sodium borohydride.
．． Add the chicks and let stand at room temperature for 1 hour.

After the reaction is completed, ethanol is removed. Add water to the residue to decompose it, and extract with chloroform. After washing the extract with water and drying, chloroform was distilled off, and TLC (benzene)
2' of Rfol oo-spiro[cyclohexane-1
, 9'monothioxanthene)-4-ol is obtained as a clay oil. 21 Chlorose Spiro [Cyclohexane-1
, 32.6 g of 9-thioxanthene]-4-ol was dissolved in 180 g of pyridine, and while cooling, 13.1 g of methanesulfonyl chloride was added dropwise little by little. After cooling at room temperature for 1 hour, the reaction solution was added to ice water. , extracted with ethyl acetate.

The extract was washed with dilute hydrochloric acid and cold water in that order, dried, and ethyl acetate was distilled off. TLC (benzene) showed Rfo. 2' of 5
Monochloro-4-mesyloxy-spiro [cyclohexane-1,9'-monothioxanthene] is obtained as a viscous oil. Example 2 2'-chloro-4-mesyloxy-spiro [cyclohexane-1,9'-monothioxanthene]4. Female, 4-(4-
2.5 g of chloro-3-trifluoromethylphenyl)-4-piveridinol, 1. Crab, potassium iodide 1. Then, heat the mixture with 20 ml of toluene under reflux for 9 hours.

After washing the toluene layer with water and drying, the toluene is removed. The residual light is separated and purified by column chromatography (using silica gel; developing solvent: chloroform-methanol (9:1)). When the obtained target base is converted into a hydrochloride salt using a conventional method, 2'chloro4 is formed as white crystals with a melting point of 279°C (decomposition).
1[4-(4-chloro-3-trifluoromethylphenyl)-4hydroxypiveridino]-spiro[cyclohexane-1,9'-monothioxanthene] hydrochloride is obtained. Examples of compounds produced in the same manner as the above examples: {1,
2'Chloro4-[4-(5-chloro.-2-oxo-1
(1benzimidazolinyl)piveridino]-spiro[2-cyclohexane-1,9'-thioxanthene], hydrochloride, melting point 290 qo (decomposition) (212' qo.

Claims (1)

[Claims] 1 Thioxanthene derivatives and their salts represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the above formula, each symbol is as follows. X is halogen, Y is hydrogen The dotted line in ring A indicates that this part may form a double bond. Z indicates the group of the formula ▲ Numerical formula, chemical formula, table, etc. ▼ Here, R^1 is halogen, R^2 represents trifluoromethyl, and R^3 represents halogen.