JPH0357902B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel benzoxazolone derivatives. The benzoxazolone derivative of the present invention is represented by the following general formula [1]. [In the formula, R ₁ is a phenyl group that may have 1 to 3 substituents selected from a halogen atom, a lower alkoxy group, and a lower alkyl group, and R ₂ is a lower alkyl or

[Formula] group (R ₁ is the same as above) and A represent a lower alkoxy group] As the halogen atom as a substituent of the substituted phenyl group defined by R ₁ in the above general formula [1],
Fluorine atom, bromine atom, chlorine atom and iodine atom are used as lower alkyl groups such as methyl, ethyl,
Examples of lower alkoxy groups include propyl, butyl, tert-butyl, pentyl, hexyl, etc.; methoxy, ethoxy, propoxy, butoxy, tert-
Examples include butoxy, pencyloxy, hexyloxy and the like. Examples of the lower alkyl group defined for R ₂ include those mentioned above. Examples of the lower alkoxy group defined by A include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene groups. Among the definitions defined for R ₁ above, preferred examples include phenyl group; monohalogenophenyl group (2-, 3- or 4-fluorophenyl group, 2-, 3- or 4-bromophenyl group,
2-, 3- or 4-chlorophenyl group, 2
-, 3- or 4-iodophenyl group); dihalogenophenyl group (2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 2,5-dichlorophenyl group, 2,6-dichloro phenyl group,
3,4-dichlorophenyl group, 3,5-dichlorophenyl group, etc.); trihalogenophenyl group (2,
3,4-trichlorophenyl group, 2,3,5-trichlorophenyl group, 2,3,6-trichlorophenyl group, 3,4,5-trichlorophenyl group,
3,4,6-trichlorophenyl group, etc.); mono-lower alkoxyphenyl group (2-, 3- or 4-trichlorophenyl group, etc.);
-methoxyphenyl group, 2-, 3- or 4-
Ethoxyphenyl group, 2-, 3- or 4-propoxyphenyl group, 2,3- or 4-butoxyphenyl group, 2-, 3- or 4-tert-
Butoxyphenyl group, 2-, 3- or 4-pentyloxyphenyl group, 2-, 3- or 4
-hexyloxyphenyl group); di-lower alkoxyphenyl group (2,3-diethoxyphenyl group, 2,4-diethoxyphenyl group, 2,5-diethoxyphenyl group, 2,6- Diethoxyphenyl group, 3,4-diethoxyphenyl group, 3,5-
diethoxyphenyl group, etc.); tri-lower alkoxyphenyl group (2,3,4-triethoxyphenyl group, 2,3,5-triethoxyphenyl group, 2,
3,6-triethoxyphenyl group, 3,4,5-
triethoxyphenyl group, 3,4,6-triethoxyphenyl group, etc.); mono-lower alkyl group (2-,
3- or 4-methylphenyl group, 2-,3-
or 4-ethylphenyl group, 2-3- or 4-propylphenyl group, 2-, 3- or 4-butylphenyl group, 2-, 3- or 4-
tert-butylphenyl group, 2-, 3- or 4
-pentylphenyl group, 2-, 3- or 4-
hexyl phenyl group, etc.); di-lower alkyl phenyl group (2,3-dimethylphenyl group, 2,4-dimethylphenyl group, 2,5-dimethylphenyl group, 2,6-dimethylphenyl group, 3, 4-dimethylphenyl group, 3,5-dimethylphenyl group,
2,3-diethylphenyl group, etc.); tri-lower alkyl phenyl group (2,3,4-trimethylphenyl group, 2,3,5-trimethylphenyl group, 2,
(3,6-trimethylphenyl group, 3,4,5-trimethylphenyl group, 3,4,6-trimethylphenyl group, 2,3,4-triethylphenyl group, etc.). The benzoxazolone derivative of the present invention represented by the above general formula [1] has a central nervous system depressant effect, an antihistamine effect, an antihypertensive effect, etc., and is an analgesic, a sedative, a tranquilizer, an antipyretic, and an anticonvulsant. It is useful as an antihistamine and antihypertensive agent. The benzoxazolone derivative [1] of the present invention is
For example, it can be produced according to several methods shown in the following reaction schemes. [In the formula, R ₁ and A are the same as above. R′ ₂ represents a lower alkyl group, and X represents a halogen atom] In other words, the symbol [1′] in which R ₂ represents a lower alkyl group in the derivative of the present invention is a benzoxazolone derivative represented by the general formula [2] and the general formula [ It can be produced by reacting with the piperazine derivative shown in 3]. The reaction between the benzoxazolone derivative [2] and the piperazine derivative [3] can be carried out, for example, preferably using a basic compound as a dehydrohalogenating agent at room temperature to 200°C, preferably at 50 to 200°C in an appropriate solvent.
It takes several hours to 15 hours to carry out the process at 150°C. In the above, suitable solvents include, for example, lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; ethers such as dioxane and diethylene glycol dimethyl ether; aromatic hydrocarbons such as toluene and xylene; dimethyl formamide , dimethyl sulfoxide and the like. Basic compounds that can be used as dehydrohalogenation agents include, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium hydride, metallic potassium, sodium Examples include tertiary amines such as amide, pyridine, quinoline, triethylamine, and tripropylamine. In the above reaction, an alkali metal iodide compound such as potassium iodide or sodium iodide can also be used as a reaction promoter. Benzoxazolone derivative [2]
The proportion of the piperazine derivative [3] and the piperazine derivative [3] is not particularly limited, but it is preferable to use 1 mol or more of the latter, usually about 1 to 5 mol, per 1 mol of the former. General formula [2] used as a starting material in the above reaction
The benzoxazolone derivative [2] represented by is a new compound and can be easily produced, for example, according to the method shown in the following reaction scheme-2. [In each of the above formulas, R' ₂ and X are the same as above.
THP represents a tetrahydropyranyl group] The production of nidrodihydroxybenzene [5] from the above dihydroxybenzene [4] is carried out according to a conventional nitro reaction method. Examples of the nitrifying agent used in the nitration include concentrated nitric acid, nitric anhydride, nitric acid and concentrated sulfuric acid, fuming nitric acid, a mixture of fuming nitric acid and nitric anhydride or acetic acid, and a mixture of sulfuric acid and a nitrate such as potassium nitrate or sodium nitrate. can be exemplified. The amount of the nitrifying agent used is based on dihydroxybenzene [4], which is usually used as a raw material.
The amount is 0.5 to 1.5 times the mole, preferably about the same mole. The nitration reaction usually proceeds at a temperature of about 0 to 50°C, particularly preferably about 0 to 5°C. The production of aminodihydroxybenzene [6] from nitrodihydroxybenzene [5] is carried out by various commonly known reduction methods. As the reduction method, for example, a method using a reducing agent or a method using a hydrogenation catalyst can be exemplified, and these can be carried out either at normal pressure or under increased pressure. In the method using the above-mentioned reducing agent, preferred reducing agents include, for example, iron and hydrochloric acid, zinc and acetic acid, and stannous chloride and hydrochloric acid, among which stannous chloride and hydrochloric acid are particularly preferred. The amount of these reducing agents used is usually from an equimolar amount to the raw material nitrodihydroxybenzene [5].
The excess amount, preferably about 3 to 5 times the molar amount, is used, and the reaction is carried out at a temperature of about 0 to 150°C, preferably about 50 to 100°C. In addition, in the method using the above hydrogenation catalyst, specific examples of the hydrogenation catalyst include palladium black, palladium carbon, Raney nickel,
Examples include platinum dioxide, which are used in conventional catalytic amounts. The reaction is usually carried out in a suitable solvent such as water,
It is carried out in the presence of methanol, ethanol, isopropanol, acetic acid, etc. The reaction temperature is approximately 0 to 100°C, preferably around room temperature. The production of hydroxybenzoxazolone [7] by the ring-closing reaction of aminodihydroxybenzene [6] obtained above is generally carried out without a solvent or in a suitable solvent such as carbon tetrachloride, chloroform, methylene dichloride, etc., using urea, phosgene, chloroform, etc. This is carried out by allowing a ring-closing agent such as ethyl carbonate to act on aminodihydroxybenzene [6] in an amount of approximately equimolar to 5 times the molar amount. The ring-closing reaction is usually carried out at about 80 to 200°C, preferably about 120 to 160°C.
Progresses well at temperatures of . The subsequent introduction of a protecting group into the hydroxyl group of hydroxybenzoxazolone [7] is carried out using, for example, 2,3-dihydropyran in a suitable solvent in the presence of a catalyst. Specific examples of solvents include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, 1,2-dimethoxyethane, and dioxane; n-hexane, cyclohexane, methylene chloride, chloroform, dimethylformamide, and hexamethyl. Examples include phosphoric acid triamide and dimethyl sulfoxide. Specifically, the catalysts include inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, and phosphoric acid; organic acids such as acetic acid, p-toluenesulfonic acid, and methanesulfonic acid; phosphorus oxychloride, aluminum chloride, zinc chloride, and Examples include Lewis acids such as boron fluoride; thionyl chloride; and the like. The above protecting group introduction reaction is carried out using at least an equimolar amount of 2,3-dihydropyran and a catalyst of about 0.1 to 5% by weight, preferably about 0.5 to 3% by weight, based on the raw material [7]. C. to the boiling point of the solvent, preferably at a temperature in the range of about room temperature to about 50.degree. C., and takes about 1 to 6 hours. Compound [8] obtained from the above and the compound

The reaction with [9], that is, the reaction of introducing an alkyl group (R' ₂ group) into the nitrogen atom of compound [8], is carried out, for example, in the presence of a basic compound in a suitable solvent. Examples of the basic compound include sodium hydride, potassium, sodium, sodium amide, potassium amide, and the like. Examples of the solvent include ethers such as dioxane and diethylene glycol dimethyl ether; aromatic hydrocarbons such as toluene and xylene; dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. Compound [8] and compound

The proportion of [9] to be used is not particularly limited and can be appropriately selected within a wide range, and it is usually advisable to use at least an equimolar amount of the latter to the former, preferably an equimolar to twice the molar amount of the latter. The reaction is usually carried out at a temperature of about 0 to 70°C, preferably from about 0°C to room temperature, and is generally completed in about 0.5 to 12 hours. The last step, the removal of the protecting group from compound [10], is carried out using aromatic solvents such as benzene, toluene, and xylene; ether solvents such as n-hexane, cyclohexane, diethyl ether, 1,2-dimethoxyethane, and dioxane. The reaction is carried out using an acid in a solvent; an alcoholic solvent such as methanol, ethanol, or propanol; a solvent such as chloroform, dimethylformamide, hexamethylphosphoric triamide, or dimethyl sulfoxide, or a mixed solvent of this and water. Examples of acids include hydrochloric acid, sulfuric acid, phosphoric acid,
Inorganic acids such as hydrobromic acid; organic acids such as acetic acid, p-toluenesulfonic acid, and methanesulfonic acid are widely used, but inorganic and organic weak acids are preferred. The amount of acid used is not particularly limited and is preferably in excess of compound [10]. The reaction is usually carried out at room temperature to the boiling point of the solvent, preferably at room temperature to 50°C. In this way, the raw material compound [2] for producing the derivative of the present invention can be obtained according to the reaction scheme-1. Furthermore, R ₂ in the derivative of the present invention is

A compound representing the group [Formula] can be produced according to the following reaction scheme-3. [In the formula, R ₁ , A and X are the same as above. R″ ₂ is

[Formula] represents a group (R ₁ is the same as above)] In the reaction shown in the above reaction scheme-3, at least an equimolar amount of the piperazine derivative [3] is added to the hydroxybenzoxazolone [7], preferably about 2 The reaction scheme is as follows except that ~4 times the molar amount is used.
It is carried out under the same reaction conditions as in 1. Thus, in the general formula [1] of the present invention, R ₂ is

[Formula] A compound [1″] which is a group can be obtained. Also, a benzoxazolone derivative [1] of the present invention
can also be produced according to the method shown in Reaction Scheme-4 below. [In the formula, R ₃ represents a lower alkyl group or -AX group. R ₁ , A, X and R ₂ are the same as above] In the above reaction scheme-4, the present derivative [1] is obtained by reacting a halogenoalkoxybenzoxazolone derivative [11] with a known piperazine derivative [12]. Manufactured by The reaction is completed in a few hours to about 24 hours without a solvent or in a common inert solvent at a temperature of 0 to 200°C, preferably room temperature to 100°C. Examples of inert solvents include ethers such as dioxane, tetrahydrofuran, ethylene glycol, and dimesyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; lower alcohols such as methanol, ethanol, and isopropanol; dimethylformamide, dimethyl Polar solvents such as sulfoxides can be used. The above reaction is more advantageously carried out using a basic compound as dehydrohalogenating agent. Examples of the basic compound include potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide,
Tertiary amines such as sodium hydride, triethylamine, tripropylamine, pyridine, and quinoline can be used. Further, in the above reaction, an alkali metal iodide compound such as potassium iodide or sodium iodide may be added as a reaction promoter if necessary. The usage ratio of the halogenoalkoxybenzoxazolone derivative [11] and the piperazine derivative [12] in the above reaction is not particularly limited,
Generally, the latter may be used in an equimolar to excess amount, preferably equimolar to 5 times the molar amount of the former. The halogenoalkoxybenzoxazolone derivative [11] used as a starting material in the above reaction is
For example, it can be easily produced by the method shown in Reaction Scheme-5 above. [In the formula, R ₄ represents a hydrogen atom or a lower alkyl group,
X′ represents a halogen atom. In addition, X, A and R ₃ are the same as above] That is, the halogenoalkoxybenzoxazolone derivative [11] is the benzoxazolone derivative shown in the general formula [13] and the dihalogenoalkane derivative [14]
It is obtained by reacting with. The reaction conditions for this reaction may be the same as those for the dehydrohalogenation reaction shown in Reaction Scheme-1. In this way, the benzoxazolone derivative [1] of the present invention is obtained. The derivative [1] can be made into a pharmaceutically acceptable acid addition salt by reacting with an appropriate acid. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid;
Oxalic acid, maleic acid, fumaric acid, malic acid,
Organic acids such as tartaric acid, citric acid and benzoic acid may be mentioned. The target compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include a filter extraction method, a dilution method, a recrystallization method, column chromatography, and preparative thin layer chromatography. The benzoxazolone derivatives of the compounds of the present invention and their salts can be administered to humans and animals as they are or as active ingredients together with a conventional pharmaceutical carrier. In this case, the administration route and dosage unit form are not particularly limited, and can be administered orally or parenterally, for example, as oral preparations such as tablets, granules, and oral solutions, or parenteral preparations such as injections. The dosage of the active ingredient is appropriately determined depending on the route of administration, dosage unit form, desired pharmacological effect, and the like. Normal 1
The daily dose of active ingredient per 1 kg of body weight is approximately 40μ
g to 5 mg, which can be administered in divided doses 3 to 4 times a day. The above-mentioned dosage unit form can be easily manufactured according to conventional methods, and the carriers that can be used at that time may also be conventional ones. For example, tablets contain active ingredients such as gelatin, starch, lactose, magnesium stearate,
It is shaped by mixing with excipients such as talcum and gum arabic. Capsules are prepared by mixing the active ingredient with an inert manufacturing filler or diluent and filling the mixture into hard gelatin capsules, soft capsules, and the like. Furthermore, drugs for parenteral administration such as injections are manufactured by dissolving or suspending the active ingredient in a sterilized liquid carrier. The preferred carrier is water or saline. Reference Examples and Examples will be given below to explain the present invention in more detail, but the present invention is not limited thereto. Reference Example 1 Production of 3-nitrocatechol Dissolve 50 g of catechol in 2.5 g of diethyl ether, add 20 ml of fuming nitric acid under cooling, and leave to stand for 12 hours. After that, the reaction was washed with water, and after drying, diethyl ether was removed, and 200 ml of chloroform was added to the residue.
The precipitated crystals were separated and the chloroform solution was applied to a Schiot column to obtain 3-nitrocatechol. yield
29g, melting point 78-80℃ Reference Example 2 Production of 3-aminocatechol hydrochloride Dissolve 29g of 3-nitrocatechol in a mixture of 150ml of water, 600ml of ethanol, and 50ml of hydrochloric acid, and catalytically reduce the solution using 6g of 5% palladium on carbon. . After the reaction is completed, the catalyst is separated and the reaction solution is distilled to obtain 28 g of 3-aminocatechol hydrochloride. Melting point: 214°C (decomposition) Reference example 3 Production of 7-hydroxy-2(3H)-benzoxazolone 28 g of 3-aminocatechol hydrochloride and 35 g of urea
and heated at 140-150°C for 3 hours. After the reaction is complete, add 100 ml of water, collect the precipitated crystals, and wash with water. _H2O
Recrystallization from the solution yields 15 g of 7-hydroxy-2(3H)-benzoxazolone. Melting point 236-240℃ Reference example 4 7-tetrahydropyranyloxy-2(3H)-
Preparation of benzoxazolone 3.8 g of 7-hydroxy-2(3H)-benzoxazolone are suspended in 40 ml of methylene chloride, and 4.2 g of dihydropyran is added thereto, followed by a catalytic amount of concentrated sulfuric acid. After reacting at room temperature for 1 hour and removing the precipitated crystals, add to 7.5% potassium carbonate aqueous solution,
Stir for 2 hours. The crystals were collected, washed with water, and recrystallized from ethanol to obtain 2.3 g of 7-tetrahydropyranioxy-2(3H)-benzoxazolone. Melting point: 228-230°C Reference Example 5 Production of 3-methyl-7-tetrahydropyranyloxy-2-benzoxazolone 560 ml of sodium hydride was suspended in 25 ml of dimethylformamide, and 7-tetrahydropyranyloxy-2 (3H )-Benzoxazolone 23g
After stirring at room temperature for 1 hour, add 6 g of methyl iodide.
was added and reacted for 1 hour, then the reaction product was poured into water, the precipitated crystals were collected, washed with water, dried, and recrystallized from ethanol to obtain 21 g of 3-methyl-7-tetrahydropyrahyloxy-2-benzoxazolone. obtain. Colorless scaly crystals, melting point 126-129°C Reference example 6 Production of 3-methyl-7-hydroxy-2-benzoxazolone 1 g of 3-methyl-7-tetrahydropyranyloxy-2-benzoxazolone was added to 10 ml of ethanol.
After adding a catalytic amount of concentrated sulfuric acid and stirring at room temperature for 3 hours, the ethanol was distilled off, and water was added to the residue to collect crystals. This was recrystallized from ethanol to obtain 670 mg of 3-methyl-7-hydroxy-2-benzoxazolone. colorless prismatic crystals,
Melting point 210-212℃ Reference example 7 7-(3-chloropropoxy)-3-methyl-2
-Production of benzoxazolone 0.5 g of 3-methyl-7-hydroxy-2-benzoxazolone was dissolved in 5 ml of dimethylformamide, 0.8 g of potassium carbonate was added thereto, and after stirring at room temperature for 1 hour, 1,3-promochloropropane
Add 1.0 g and stir for further 8 hours at room temperature. The reaction product was poured into ice water, the precipitated crystals were collected, washed with water and hexane, and recrystallized from ethanol.
0.6 g of -(3-chloropropoxy)-3-methyl-2-benzoxazolone is obtained. Colorless prismatic crystals, melting point 109-110°C Reference example 8 Production of 3-(3-chloropropyl)-7-(3-chloropropoxy)-2-benzoxazolone 2 g of 7-hydroxy-2(3H)-benzoxazolone, 3.2 g of 1,3-bromochloropropane and 2.7 g of potassium carbonate were mixed with 20 g of dimethylformamide.
ml and left overnight at room temperature, the reaction mixture was poured into water, the precipitated crystals (2.0 g) were collected, washed with water, dried, and recrystallized from a ligroin-benzene mixture to give 3-(3-chloro 1.5 g of propyl)-7-(3-chloropropoxy)-2-benzoxazolone are obtained. Melting point: 78-80°C Example 1 1.0 g of 3-methyl-7-hydroxy-2-benzoxazolone, 1-(4-phenylpiperazine-
2.0 g of 1-yl)-3-bromopropane and 1.6 g of potassium carbonate were suspended in 20 ml of dimethylformamide, heated and stirred at 80 to 90°C for 18 hours, dried under reduced pressure, and an aqueous sodium bicarbonate solution was added to precipitate crystals. was collected and recrystallized from ethanol to give 3-methyl-7-[3-(4-phenylpiperazin-1-yl)-propoxy]-2-benzoxazolone 0.4
get g. Crystal form: Colorless flaky crystal Melting point: 111-112°C Example 2 3-Methyl-7-(3-chloropropoxy)-2
- Suspend 1.2 g of benzoxazolone and 1.2 g of sodium iodide in 30 ml of acetone, reflux this for 3 hours, dry under reduced pressure, and add 30 ml of dimethylfomulamide.
and further added 1.1 g of phenylpiperazine and 0.8 g of triethylamine, heated at 80 to 90°C for 35 hours, dried under reduced pressure, and then repeated the same operation as in Example 1 to obtain 3-methyl-7-[3 0.6 g of -(4-phenylpiperazin-1-yl)-propoxy]-2-benzoxazolone is obtained. Crystal form: Colorless scale crystal Melting point: 111-112°C Examples 3-5 In the same manner as in Examples 1 and 2, the derivatives of the present invention shown in Table 1 below were obtained from appropriate starting materials.

【table】

[Table] Example 6 1.5 g of 3-(3-chloropropyl)-7-(3-chloropropoxy)-2-benzoxazolone and 1.7 g of sodium iodide were suspended in 30 ml of acetone,
After heating under reflux for 3 hours, the mixture was dried under reduced pressure, and 20 ml of dimethylformamide was added thereto, followed by 2.3 g of phenylpiperazine and 4.5 g of triethylamine. After heating at 80 to 90°C for 4 hours, the mixture was dried under reduced pressure and Extracted by adding aqueous sodium hydrogen solution and chloroform, purified by column, recrystallized from ethanol to obtain 3-[3-(4-phenylpiperazine-
0.7 g of 1-yl)propyl]-7-[3-(4-phenylpiperazin-1-yl)propoxy-2-benzoxazolone is obtained. Melting point: 97-98℃

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ is a phenyl group that may have 1 to 3 substituents selected from a halogen atom, a lower alkoxy group, and a lower alkyl group, and R ₂ is a lower alkyl or [Formula] group (R ₁ is the above-mentioned ) and A represents a lower alkylene group] A benzoxazolone derivative characterized by being represented by: