JPS625429B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel allofanoylpiperazine compound and an analgesic containing the same as an active ingredient. The allofanoylpiperazine compound according to the present invention is represented by the following general formula. (In the formula, R ¹ is a lower alkyl group or a phenyl group, R ² and R ³ are a hydrogen atom or a lower alkyl group, R ⁴ is a phenyl group, a halogen atom, a methyl group, a trifluoromethyl group as a substituent, hydroxyl group,
Phenyl group having methoxy group, methylenedioxy group, nitro group or carboxyl group, pyridyl group, pyrimidinyl group, thiazolyl group, benzyl group, cinnamyl group, cyclohexyl group, lower alkyl group, lower having chlorine atom or hydroxyl group as a substituent It means an alkyl group or a lower alkenyl group. (Hereinafter, the same symbols mean the same thing) The above compound in the present invention is a new compound that has not been described in any literature, and it not only has an analgesic effect and is useful as an analgesic, but also has an anti-inflammatory effect. There is. Conventionally, as well as the allofanoylpiperazine compound represented by the general formula (1), There have been no reports on the compound itself having this skeleton. The present inventor has conducted intensive research on this type of allofanoylpiperazine compound with the aim of developing a compound with analgesic effect, and has discovered that the compound represented by the general formula (1) can be suitable for that purpose. , we have completed the present invention. The allofanoylpiperazine compound in the present invention can be synthesized by any of the methods exemplified below. Method A is characterized by reacting allofanoyl chloride represented by general formula (2) with piperazine represented by general formula (3), and is represented by the following reaction formula. In the above formula, the reaction between allofanoyl chloride (2) and piperazine (3) is usually carried out in a solvent. The solvent is not particularly limited as long as it does not participate in the reaction, but generally ethyl ether,
Ethers such as dioxane and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride, benzene, toluene,
Aromatic hydrocarbons such as xylene are used.
In the reaction, if necessary, a suitable condensation auxiliary substance such as a basic compound such as trialkylamine or pyridine is used. The ratio of allofanoyl chloride (2) and piperazine (3) to be used may be selected as appropriate, but it is generally recommended to use about 1 to 2 times the molar amount of piperazine (3) to allofanoyl chloride (2). It's advantageous. Although the reaction temperature may be selected appropriately, the reaction generally proceeds advantageously when carried out at about -20 to 50°C. Method B Isocyanate represented by general formula (4) and general formula (5)
It is characterized by reacting with urea shown in
It is expressed by the following reaction formula. However, this method is applied only when R ² is a hydrogen atom. In the above formula, the reaction between isocyanate (4) and urea (5) is usually carried out in a solvent in the presence of a catalyst. The catalyst is generally anhydrous aluminum chloride,
Lewis acids such as anhydrous stannic chloride and titanium tetrachloride are preferably used. The solvent is not particularly limited as long as it does not participate in the reaction, but halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, and xylene are generally used. . The proportions of isocyanate (4), urea (5) and catalyst to be used may be selected as appropriate, but it is generally advantageous to use equimolar amounts. Although the reaction temperature may be selected appropriately, the reaction generally proceeds advantageously when carried out at about -20°C to room temperature. Method C is characterized by reacting allofanoylpiperazine represented by general formula (6) with a halogen compound represented by general formula (7) (X means a halogen atom), and is represented by the following reaction formula. . However, this law
This does not apply when R ⁴ is a phenyl group or a phenyl group having a substituent. In the above formula, the reaction between allofanoylpiperazine (6) and halogen compound (7) is usually carried out in a solvent in the presence of a basic compound. Examples of basic compounds include trialkylamine, pyridine,
Alkali carbonate etc. are used. The solvent is not particularly limited as long as it does not participate in the reaction, but generally lower alcohols such as methanol, ethanol, and propanol, halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride,
Aromatic hydrocarbons such as benzene, toluene, and xylene are used. Allofanoylpiperazine
The proportions of (6), halogen compound (7) and basic compound to be used may be selected as appropriate, but it is generally advantageous to use equimolar amounts. Although the reaction temperature may be selected appropriately, the reaction generally proceeds advantageously when carried out at a temperature of -20°C to about the boiling point of the solvent. Allofanoylpiperazine (6) used as a raw material in this reaction is a new compound, which uses 1-formylpiperazine (8) as a starting material,
A compound represented by the general formula (9) is prepared according to the above method A or method B, and then deformylated according to a known method (Yakugaku Zasshi 74, 1049-1052 (1954)). easily obtained. The above methods A to C produce the allofanoylpiperazine compound (1) according to the present invention, which can be easily isolated by conventional separation means. The dosage of the analgesic according to the present invention is usually 0.5 to 1000 mg per day for adults, preferably 1 to
The dose is 500 mg, which is divided into 1 to 4 doses. The dosage is adjusted depending on the individual case, taking into account the patient's condition, age, etc. Administration is carried out in various forms such as oral preparations, injections, suppositories for rectal administration, and external preparations. The analgesic according to the present invention is prepared as a composition containing any conventional pharmaceutical carrier or excipient by a commonly used method, and then used. More specifically, tablets, capsules, granules, powders, etc. for oral administration may contain excipients commonly used in the art, such as calcium carbonate, calcium phosphate, starch, sucrose, lactose, talc, Magnesium stearate, gelatin, polyvinylpyrrolidone, gum arabic, sorbitol, microcrystalline cellulose, polyethylene glycol, carboxymethylcellulose, silica, polyvinyl acetal diethylaminoacetate,
It may also contain hydroxypropyl methylcellulose, citric acid, and the like. The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may be aqueous or oily suspensions, solutions, syrups, elixirs, and the like, and are prepared by commonly used methods. Injectables may be aqueous or oily suspensions, solutions, powder fillers to be dissolved at the time of use, freeze-dried agents, etc., and are prepared by commonly used methods. For rectal administration, the composition may be provided as a suppository and may contain pharmaceutical carriers well known in the art, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglycerides, and the like. External preparations are preferably administered in the form of ointments or creams, and are prepared by adding commonly used bases and the like by conventional methods. Hereinafter, the present invention will be described in more detail with examples of synthesis of the allofanoylpiperazine compound represented by the general formula (1), analgesic test and formulation examples of the allofanoylpiperazine compound synthesized thereby. explain. Synthesis examples of the allofanoylpiperazine compound represented by the general formula (1) by methods A, B, and C are as follows, and the compounds obtained by these synthesis examples and the compounds obtained according to these synthesis examples The physical properties of the obtained compound were as shown in Table 1. Synthesis Example 1 by Method A (Synthesis Example of Compound No. 6 in Table 1) 1-phenylpiperazine in 40ml of dichloromethane
6.5 g was dissolved, and 3.0 g of 2,4-dimethylallophanoyl chloride was added dropwise while stirring under ice cooling. After reacting for 0.5 hour at room temperature, the reaction solution is washed with water. After drying over anhydrous sodium sulfate, the solvent was distilled off and the residue was recrystallized from ethanol-petroleum ether to give 4.0 g of 1-(2,4-dimethylallophanoyl)-4-phenylpiperazine with a melting point of 79-80°C.
(yield 72%). 2 (Synthesis example of compound No. 19 in Table 1) 10.8 g of 1-(p-fluorophenyl)piperazine and 6.1 g of triethylamine in 80 ml of dichloromethane.
g was dissolved, and 10.0 g of 2,4,4-trimethylallophanoyl chloride was added dropwise while stirring under ice cooling. After reacting for 1 hour at room temperature, the reaction solution was washed with water. After drying over anhydrous sodium sulfate, the solvent was distilled off and the residue was recrystallized from ethanol-ether to give 1-(p-fluorophenyl)- with a melting point of 83-84°C.
4-(2,4,4-trimethylallophanoyl)
13.7 g (yield 74%) of piperazine was obtained. Synthesis Example 1 by Method B (Synthesis Example of Compound No. 1 in Table 1) 4.1 g of 4-phenylpiperazine-1-carboxamide and 1.2 g of methyl isocyanate were dissolved in 70 ml of dichloromethane, and the solution was anhydrous with stirring under ice cooling. Add 5.2 g of stannic chloride dropwise. After reacting at room temperature for 15 hours, water was added and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was recrystallized from ethanol to obtain 1.
2.7 g (yield 51%) of -(4-methylallophanoyl)-4-phenylpiperazine was obtained. 2 (Synthesis example of compound No. 12 in Table 1) Dissolve 4.3 g of 1-(methylcarbamoyl)-4-(m-trifluoromethylphenyl)piperazine and 0.9 g of methyl isocyanate in 70 ml of dichloromethane, and cool on ice. Anhydrous stannic chloride 3.9 with stirring under
Drop g. After reacting at room temperature for 15 hours, the precipitate was collected and added to a dichloromethane-water mixed solution and stirred. The organic layer was separated, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was recrystallized from ethanol-petroleum ether to give 1-(2,4-dimethylallophanoyl)- with a melting point of 97-98°C. 4-
(m-trifluoromethylphenyl)piperazine
3.2g (yield 62%) was obtained. Synthesis Example 1 by Method C (Synthesis Example of Compound No. 44 in Table 1) Add 5.0 g of 1-(2,4,4-trimethylallophanoyl)piperazine hydrochloride and 3.7 g of sodium carbonate to 20 ml of ethanol, and stir. While doing so, 2.5 g of isopropylbromide is added dropwise. After reacting under reflux for 8 hours, the precipitate was removed. Concentrate the liquid and purify the residue using a silica gel column to obtain an oil. This is converted into a hydrochloride salt by a conventional method, and recrystallized from ethanol to give a 1-
(isopropyl)-4-(2,4,4-trimethylallophanoyl)piperazine hydrochloride 3.8 g (yield
65%). Note that 1-(2,4,4-trimethylallophanoyl)piperazine hydrochloride used above was synthesized by the following method. Dissolve 41 g of 1-formylpiperazine and 54.5 g of triethylamine in 600 ml of tetrahydrofuran,
While stirring under ice-cooling, 56 g of 2,4,4-trimethylallophanoyl chloride is added dropwise. After reacting at room temperature for 6 hours, the precipitate is removed. The liquid was concentrated, and the residue was recrystallized from tetrahydrofuran to give 1
41 g of -formyl-4-(2,4,4-trimethylallophanoyl)piperazine are obtained. This is 6N
-Add to 800 ml of HC, heat and stir at 60°C for 1 hour, and then concentrate. Ethanol was added to the residue to remove insoluble matter, the liquid was concentrated, and the residue was recrystallized from ethanol to obtain 35.2 g of 1-(2,4,4-trimethylallophanoyl)piperazine hydrochloride having a melting point of 215°C. Ta. Elemental analysis (as C ₉ H ₁₈ N ₄ O ₂・HC) C H H Calculated value (%) 43.11 7.64 22.35 Actual value (%) 42.92 7.90 22.11

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[Table] The test methods for analgesic effect and acute toxicity were as follows, and the results were as shown in Table 2. Analgesic effect 1 Acetic acid stretching method Koster et al.'s method [Fed.Pro., 18, 412
(1959)], DDY male mice (body weight 20~
25g), and 100mg/Kg of the drug was administered orally.
After an hour, add 0.35 ml of 0.6% acetic acid per animal.
Each drug was administered intraperitoneally, and the stretching symptoms were observed to determine the inhibition rate (%). The values marked with * in Table 2 indicate the 50% effective dose ED ₅₀ (mg/Kg), and NT means not tested. 2 Hafner method Modified method by Fujimura et al. [Kyoto University Chemical Research Institute Report No. 25]
36 (1951)], a threshold dose of morphine hydrochloride (2.5 mg/Kg) was administered subcutaneously to male ddy mice (body weight 20-25 g) 30 minutes after orally administering 100 mg/Kg of the drug. After that, the pain response due to the cream was observed for 1 hour, and the suppression rate (%) was determined. The values marked with * in Table 2 are 50% effective dose ED ₅₀
(mg/Kg), NT means not tested. Acute toxicity The acute toxicity test was conducted using male DDY mice (body weight 20~
The drug was administered orally. General symptoms after administration were observed for 7 days and expressed as number of deaths/number of animals in one group relative to dose (mg/Kg). Table 2
The value marked with an asterisk (*) is the 50% lethal dose LD ₅₀ (mg/Kg)
shows. In the above tests, all drugs were 0.1-0.25
% carboxymethyl cellulose solution or suspended therein.

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[Table] Finally, some formulation examples of the allofanoylpiperazine compound according to the present invention are listed. Formulation Example 1 Compound 22 5 mg Lactose 695 mg Corn starch 280 mg Hydroxypropyl cellulose 20 mg 1000 mg per package Granules are prepared using the above blending ratio in a conventional manner. Formulation Example 2 Compound 17 10 mg Lactose 85 mg Crystalline cellulose 50 mg Hydroxypropyl starch 30 mg Talc 4 mg Magnesium stearate 1 mg 180 mg per tablet Tablets are prepared using the above blending ratio in a conventional manner. Formulation Example 3 Compound 28 100mg Lactose 50mg Potato starch 50mg Crystalline cellulose 109mg Magnesium stearate 1mg 400mg per capsule Capsules are prepared using the above blending ratio in a conventional manner. Formulation Example 4 Compound 22 10mg Witepsol W-35 990mg (trade name manufactured by Dynamite Nobel) 1000mg per unit Suppositories are prepared according to the usual method using the above compounding ratio. Formulation Example 5 Compound 14 5mg Sodium chloride 18mg Distilled water for injection Appropriate amount 2ml per tube Prepare an injection according to the usual method at the above mixing ratio. Formulation example 6 Compound 30 2.0g White petrolatum 23.0g Stearyl alcohol 22.0g Propylene glycol 12.0g Sodium lauryl sulfate 1.5g Ethyl paraoxybenzoate 0.025g Propyl paraoxybenzoate 0.015g Purified water Appropriate amount Ointment according to the usual method with the above mixing ratio Prepare.

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is a lower alkyl group or a phenyl group, R ² and R ³ are a hydrogen atom or a lower alkyl group, R ⁴ is a phenyl group, a halogen atom, a methyl group, a trifluoromethyl group as a substituent, hydroxyl group,
Phenyl group having methoxy group, methylenedioxy group, nitro group or carboxyl group, pyridyl group, pyrimidinyl group, thiazolyl group, benzyl group, cinnamyl group, cyclohexyl group, lower alkyl group, lower having chlorine atom or hydroxyl group as a substituent An allofanoylpiperazine compound represented by an alkyl group or a lower alkenyl group. 2 General formula (In the formula, R ¹ is a lower alkyl group or a phenyl group, R ² and R ³ are a hydrogen atom or a lower alkyl group, R ⁴ is a phenyl group, a halogen atom, a methyl group, a trifluoromethyl group as a substituent, hydroxyl group,
Phenyl group having methoxy group, methylenedioxy group, nitro group or carboxyl group, pyridyl group, pyrimidinyl group, thiazolyl group, benzyl group, cinnamyl group, cyclohexyl group, lower alkyl group, lower having chlorine atom or hydroxyl group as a substituent An analgesic containing an allofanoylpiperazine compound represented by an alkyl group or a lower alkenyl group as an active ingredient.