JPS643195B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel aniline derivatives and salts thereof. The compound of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula. [In the formula, R ¹ represents a hydrogen atom or a lower alkoxycarbonyl group, R ² represents a lower alkoxy group, A represents a lower alkylene group, and n represents 1 or 2, respectively. ] Aniline derivatives represented by the above general formula (1) and their salts have an effect of enhancing myocardial contraction (positive inotropic effect) and an effect of increasing coronary blood flow, and therefore are effective against heart diseases such as congestive heart failure. It is effective as a cardiotonic agent for the treatment of. In particular, the compounds of the present invention are characterized by not causing an increase in heart rate and having low toxicity. Examples of the lower alkoxycarbonyl group shown herein include methoxycarbonyl,
Ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
Examples include alkoxycarbonyl groups having an alkoxy group having 1 to 6 carbon atoms, such as tert-butoxycarbonyl, benzyloxycarbonyl, and hexyloxycarbonyl groups. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, and isopropoxy. , butoxy, tert-butoxy, pentyloxy, hexyloxy and other alkoxy groups having 1 to 6 carbon atoms, and lower alkylene groups include, for example, methylene,
Examples include alkylene groups having 1 to 6 carbon atoms such as ethylene, trimethylene, 2-methyltrimethylene, tetramethylene, 1-methyltetramethylene, pentamethylene, and hexamethylene groups. The compound of the present invention represented by the above general formula (1) can be produced, for example, by the method shown in the following reaction scheme. Reaction equation 1 [In the formula, R ¹ , R ² , A and n are the same as above. X represents a halogen atom. ] That is, the compound of the present invention represented by the general formula (1) is produced by reacting the anilide derivative represented by the general formula (2) with the piperazine derivative represented by the general formula (3). The above reaction can be carried out in a common inert solvent from room temperature to
Under a temperature condition of about 100℃, preferably room temperature to 80℃,
It will be completed in about 1 hour to 24 hours. Examples of inert solvents include dioxane, tetrahydrofuran,
Ethers such as ethylene glycol dimethyl ether and diethyl ether, benzene, toluene,
Aromatic hydrocarbons such as xylene, lower alcohols such as methanol and ethanol, polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, acetone, and acetonitrile can be used. The above reaction is more advantageously carried out using a basic compound as a deoxidizing agent. Examples of the basic compound include potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride,
Examples include tertiary amines such as triethylamine, triprobylamine, pyridine, and quinoline. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide or hexamethylphosphoric acid triamide as a reaction promoter, if necessary. The ratio of the compound represented by the general formula (2) and the compound represented by the general formula (3) in the above reaction is not particularly limited and is appropriately selected within a wide range, but usually the latter is used in equimolar amounts to the former. The excess amount is preferably from equimolar to 5 times the mole, more preferably from 1 to 1.2 times the mole. The compounds of general formulas (2) and (3) used in Reaction Scheme-1 are, for example, the following Reaction Schemes-2 and 3.
It is easily produced by the method shown in . Reaction equation 2 [In the formula, R ¹ , A and X are the same as above. ] The compound represented by the general formula (2) is produced by subjecting a known aniline derivative represented by the general formula (4) to a carboxylic acid derivative represented by the general formula (5) and a normal amide bond forming reaction. . In this case, a compound whose carboxyl group is activated may be used instead of the compound of general formula (5), and a compound whose amino group is activated may be used instead of the compound of general formula (4). Good too. For the amide bond-forming reaction, conditions for ordinary amide bond-forming reactions can be adopted, such as (a) mixed acid anhydride method, that is, reacting the carboxylic acid (5) with an alkyl halocarboxylic acid to form a mixed acid anhydride. and (b) active ester method, in which carboxylic acid (5) is reacted with a compound of general formula (4), for example, p-nitrophenyl ester, N
- A method in which an active ester such as hydroxysuccinimide ester or 1-hydroxybenzotriazole ester is reacted with a compound of general formula (4); ) is subjected to dehydration condensation in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole. ), (e) Other methods include carboxylic acid (5)
is converted into a carboxylic acid anhydride using a dehydrating agent such as acetic anhydride, and this is reacted with a compound of general formula (4), or an ester of carboxylic acid (5) with, for example, a lower alcohol is reacted with a compound of general formula (4). Examples include a method of reacting under high pressure and high temperature. Among these, the mixed acid anhydride method and the carboxylic acid halide method are preferred. Examples of the alkylhalocarboxylic acids used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. The mixed acid anhydride is obtained by the usual Schotten-Baumann reaction, and the compound of general formula (2) is produced by reacting it with the compound of general formula (4) without isolation. The Schotten-Baumann reaction is usually carried out in the presence of a basic compound. As the basic compound used, compounds commonly used in the Schotten-Baumann reaction are used, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4,3,0]nonene-5 (DBN), 1,5-diazabicyclo[5,
4,0] undecene-5 (DBU), 1,4-diazabicyclo[2,2,2]octane (DABCO)
and inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate. The reaction is carried out at -20 to 100℃
The reaction time is approximately 5 minutes to 10 hours. The reaction between the obtained mixed acid anhydride and the compound of general formula (4) is −20 to
It is carried out at about 150°C, preferably 10 to 50°C, for about 5 minutes to 10 hours. Mixed anhydride methods are generally carried out in a solvent. Any solvent commonly used in the mixed acid anhydride method can be used as the solvent, and specifically, halogenated carbons such as methylene chloride, chloroform, and dichloroethane, benzene, toluene,
Aromatic hydrocarbons such as xylene, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide, etc. can be mentioned. The ratio of carboxylic acid (5), alkylhalocarboxylic acid, and the compound of general formula (4) used in this method is usually equivalent to the molar ratio; 4) Compound 1~
You may use 1.5 times the molar amount. In the carboxylic acid halide method, carboxylic acid (5) is reacted with a halogenating agent to form a carboxylic acid halide, and this carboxylic acid halide is isolated and purified, or is converted to the general formula (4) without isolation and purification. A compound of general formula (2) is produced by reacting the compound of formula (2).
The reaction between the carboxylic acid (5) and the halogenating agent is carried out without a solvent or in the presence of a solvent.
Any solvent can be used as long as it does not adversely affect the reaction, such as aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, dioxane, and tetrahydrofuran. , ethers such as diethyl ether, dimethylformamide, dimethyl sulfoxide, and the like.
As the halogenating agent, a usual halogenating agent that converts the hydroxyl group of a carboxy group into a halogen can be used, and examples thereof include thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, and phosphorus pentabromide. . The ratio of the carboxylic acid (5) and the halogenating agent to be used is not particularly limited and is selected as appropriate. However, when the reaction is carried out without a solvent, the latter is usually used in a large excess amount relative to the former, or in the solvent. When the reaction is carried out, the latter is usually used in at least an equimolar amount, preferably 2 to 4 times the molar amount of the former. The reaction temperature (and reaction time) is also not particularly limited, but is usually about room temperature to 100°C, preferably 50 to 80°C.
It is carried out at ℃ for about 30 minutes to 6 hours. The reaction between the carboxylic acid halide obtained as described above and the compound of general formula (4) is carried out in the presence of a dehydrohalogenating agent. As this dehydrohalogenating agent, a basic compound is usually used,
For example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, silver carbonate,
Alcoholates such as sodium methylate and sodium ethylate, triethylamine, pyridine, N,N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-
Diazabicyclo[4,3,0]nonene-5
(DBN), 1,5-diazabicyclo[5,4,0]
Examples include organic bases such as undecene-5 (DBU) and 1,4-diazabicyclo[2,2,2]octane (DABCO). Note that the compound of general formula (4) can also be used as a dehydrohalogenating agent by using an excess amount. The reaction may be carried out without a solvent or in the presence of a solvent. All inert solvents that do not adversely affect the reaction can be used as solvents, such as chloroform, methylene chloride, halogenated hydrocarbons such as carbon tetrachloride, diethyl ether,
Ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, esters such as methyl acetate and ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, hexamethyl phosphoric triamide, etc. Examples include aprotic polar solvents. The ratio of the carboxylic acid halide and the compound of general formula (4) is not particularly limited, but when the reaction is carried out in a solvent, the former is usually used in at least an equimolar amount to the latter, preferably equimolar to ~ Twice the molar amount is used. The reaction temperature and reaction time are also not particularly limited, but are usually around -30 to 100°C.
Preferably, it is carried out at 0 to 50°C for about 30 minutes to 12 hours. Reaction equation 3 [In the formula, R ² and n are the same as above. ] The compound represented by the general formula (3) can be obtained by reacting the compound represented by the general formula (6) with piperazine (9), or by reacting the compound represented by the general formula (6) with piperazine (9),
Alternatively, it can be obtained by debenzylating a compound represented by general formula (8) obtained by a reaction between a compound represented by general formula (6) and N-benzylpiperazine (7). The reaction between the compound of general formula (6) and piperazine (9) is
Although the same reaction conditions as for the reaction between the compound of general formula (4) and the compound of general formula (5) can be adopted, piperazine
The amount of (9) to be used is preferably about an equivalent molar amount to the compound of general formula (6). Compound of general formula (6) and N-benzylpiperazine (7)
For the reaction with, the same reaction conditions as for the reaction between the compound of general formula (4) and the compound of general formula (5) can be adopted. For debenzylation of the compound of general formula (8), a wide range of conditions can be adopted for ordinary debenzylation reactions, such as palladium-carbon, palladium-carbon, etc. in an appropriate solvent.
The reaction is carried out in the presence of a catalytic reduction catalyst such as black or platinum black at 0°C to around room temperature for about 0.5 to 5 hours. Examples of the solvent include water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane and THP, and acetic acid. The catalytic reduction catalyst is usually used in an amount of about 10 to 50% by weight based on the compound of general formula (8).
The reaction can also be accelerated by adding an acid such as concentrated hydrochloric acid into the reaction system. The compound of the present invention can also be produced by the method shown in Reaction Scheme-4 below. Reaction equation 4 [In the formula, R ¹ , R ² , A and n are the same as above. ] The reaction between the compound represented by general formula (4) and the compound represented by general formula (10) is carried out under the same reaction conditions as the reaction between the compound represented by general formula (4) and the compound represented by general formula (5). Can be adopted. General formula used in the above reaction scheme-4
The compound (10) is, for example, the following reaction scheme-5 or 6.
It is easily produced by the method shown in . Reaction equation 5 [In the formula, R ² , A, n and X are the same as above. R ³ represents a lower alkyl group. ] The reaction between the compound represented by the general formula (3) and the compound represented by the general formula (5) is carried out under the same reaction conditions as the reaction between the compound represented by the general formula (2) and the compound represented by the general formula (3). However, the amount of basic compound used as a deoxidizing agent should be at least 2 times the amount of the compound of general formula (5).
It is preferable to use twice the molar amount, preferably 2 to 4 times the molar amount. The reaction between the compound of general formula (3) and the compound represented by general formula (11) is the reaction between the compound of general formula (2) and the compound of general formula (3).
Reaction conditions similar to those for the reaction with the compound can be adopted. The hydrolysis reaction of the compound represented by the general formula (12) is usually carried out in the presence of a catalyst, and any catalyst used in ordinary hydrolysis reactions can be used. Examples include basic compounds such as sodium oxide, potassium hydroxide, and barium hydroxide, and mineral acids such as sulfuric acid, hydrochloric acid, and nitric acid. The amount of these catalysts to be used is not particularly limited and may be appropriately selected from a wide range. The hydrolysis reaction can be carried out according to conventional methods, but
It generally proceeds advantageously in a solvent. As the solvent used in this case, a wide range of solvents that do not participate in the reaction can be used, and examples thereof include water, lower alcohols such as methanol, ethanol, and isopropanol, and the like. The reaction temperature is not particularly limited and may be selected appropriately from a wide range, but is usually about room temperature to 150°C,
Preferably, the reaction is carried out at 50 to 110°C.
The reaction is generally completed in about 30 minutes to 10 hours. Reaction equation 6 [In the formula, R ² , A, n and R ³ are the same as above. ] The reaction between the compound represented by the general formula (13) and the carboxylic acid derivative of the general formula (6) is carried out in the same manner as the reaction between the compound of the general formula (4) and the carboxylic acid derivative of the general formula (5). Reaction conditions can be adopted. Further, the hydrolysis of the compound of general formula (12) is as explained in the reaction scheme-5 above. The compound of the present invention can also be used in the following reaction scheme-7.
It can also be produced by the method shown in Reaction equation 7 [In the formula, R ¹ , R ² , A and n are the same as above. ] For the reaction between the compound represented by the general formula (14) and the compound of the general formula (6), the same reaction conditions as for the reaction between the compound of the general formula (4) and the compound of the general formula (5) are adopted. can. The compound of general formula (14) used in the above reaction scheme-7 is produced, for example, by the method shown in the following reaction scheme-8. Reaction equation 8 [In the formula, R ¹ , A and X are the same as above. ] For the reaction between the compound of general formula (4) and the compound represented by general formula (15), the same reaction conditions as for the reaction between the compound of general formula (4) and the compound of general formula (5) are adopted. can. Furthermore, the reaction between the compound of general formula (2) and N-benzylpiperazine (7) and the reaction with piperazine (9) are both reactions between the compound of general formula (2) and the compound of general formula (3). Similar reaction conditions can be used. For the debenzylation of the compound represented by the general formula (16), the same reaction conditions as for the debenzylation of the compound represented by the general formula (8) can be employed. The aniline derivative of the present invention thus obtained can be easily converted into an acid addition salt by acting with a pharmaceutically acceptable acid, and the present invention also includes this acid addition salt. Examples of acids in the above include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, malonic acid, and methanesulfonic acid. Examples include organic acids such as acids and benzoic acid. The target compounds obtained in each step can be easily isolated and purified by conventional separation means. The separation means include a solvent extraction method,
Examples include dilution method, recrystallization method, distillation method, column chromatography, and preparative thin layer chromatography. Incidentally, the present invention naturally also includes optical isomers. The compound of general formula (1) is usually used in the form of a common pharmaceutical preparation. The formulation is prepared using commonly used diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections ( liquid agents, suspension agents, etc.). When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder , disintegrants such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc. absorption enhancers such as grade ammonium bases, sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite,
Examples include adsorbents such as colloidal silicic acid, purified talc, stearate, boric acid powder, and lubricants such as polyethylene glycol. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used.
For example, glucose, lactose, starch, cocoa butter,
Examples include excipients such as hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminalan agar. When forming into a suppository, a wide range of conventionally known carriers can be used, including polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. When prepared as injections, solutions and suspensions are preferably sterilized and isotonic with blood; when forming these solutions, emulsions and suspensions, this agent is used as a diluent. All those commonly used in the field can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,
Examples include polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution may be included in the cardiotonic agent, and usual solubilizing agents, buffers, soothing agents, etc. may be added. Good too. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, and other pharmaceutical agents may be included in the therapeutic agent, if necessary. The amount of the compound of general formula (1) to be contained in the cardiotonic agent of the present invention is not particularly limited and can be selected within a wide range, but it is usually 1 to 70% by weight, preferably 1 to 30% by weight based on the total composition. be. There are no particular restrictions on the method of administering the cardiac inotrope of the present invention, and administration may be carried out in a manner depending on various formulation forms, age, sex and other conditions of the patient, degree of disease, etc.
For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. In the case of injections, they are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, they can also be administered intramuscularly, intradermally, or intradermally.
Administered subcutaneously or intraperitoneally. Suppositories are administered rectally. The dosage of the cardiotonic agent of the present invention depends on the usage, the age of the patient,
The amount of the compound of general formula (1), which is an active ingredient, is usually about 0.1 to 10 mg per 1 kg of body weight per day, although it is appropriately selected depending on gender and other conditions, the severity of the disease, etc. Further, it is preferable that the dosage unit form contains 1 to 200 mg of the active ingredient. The results of pharmacological tests on the compounds of the present invention are listed below. Pharmacological Test Adult male and female mixed breed dogs weighing 8 to 13 kg are anesthetized by intravenously administering pentobarbital sodium salt at a rate of 30 mg/kg. heparin sodium salt
After intravenous administration at a rate of 1000U/Kg, death was caused by exsanguination.
The heart is removed into locks fluid. A cannula is inserted from the right coronary artery toward the sinus node artery, and the right atrium is removed together with the cannula. Next, the animals were anesthetized with pentobarbital sodium salt (30 mg/Kg, intravenous administration) and treated with heparin (1000 U/Kg,
Blood from the carotid artery of a male-male mixed-breed adult dog weighing 18 to 27 kg (intravenous administration) is led via a peristaltic pump to a cannula inserted into the right coronary artery to perfuse the right atrium. The perfusion pressure is a constant pressure of 100 mmHg.
The movement of the right atrium is measured by measuring the contractile force of the atrial muscle via a force displacement transducer under a resting tension of 2 g. Coronary blood flow is measured using an electromagnetic flowmeter. All records shall be recorded on an ink recorder. The details of this method have been reported by Chiba et al. [Japan, J.
Pharmacol, 25 , 433-439 (1975), Naunyn-
Schmiedbergs Arch.Pharmacol, 289 , 315~
325 (1975)]. The test compound is injected into the artery in a volume of 10-30μ via a rubber tube connected proximally to a cannula inserted into the right coronary artery. The positive inotropic effect of a test compound is expressed as a percent change in tension generated before compound administration, and the change in coronary blood flow is expressed as an absolute value (ml/min) from before administration. The results are shown in Table 1. Test compound No. 1 α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide monohydrochloride No. 2 ο-methoxycarbonyl-α-[4-(3,
4-dimethoxybenzoyl)-1-piperazinyl]acetanilide No. 3 Amrinone (control compound)

[Table] Reference examples and examples are listed below. Reference Example 1 38 g of anthranilic acid methyl ester and 35 g of potassium carbonate were dissolved in 300 ml of acetone-water (2:1), and chloroacetyl chloride was dissolved under ice-water cooling and stirring.
Drop 30g. After dropping, react at room temperature for 2 hours,
Add 200 ml of water to the reaction solution, cool with ice water, and collect the precipitated crystals. The crystals were washed with water and ethanol, and recrystallized from methanol to obtain 48.6 g of o-(α-chloroacetylamino)benzoic acid methyl ester in the form of colorless needles. Melting point: 97-99°C The following compound is obtained in the same manner as above. Γ α-chloroacetalinide Colorless scaly crystals (isopropanol) Melting point 135-136℃ Γ m-(α-chloroacetylamino)benzoic acid methyl ester Melting point 92.5-95℃ Γ p-(α-chloroacetylamino)benzoic acid Methyl ester Melting point 137.5-141.0℃ Reference example 2 Add 4.3g of piperazine to 50ml of ethanol,
2.3 g of o-(α-chloroacetylamino)benzoic acid methyl ester are added under stirring at ~50°C. After stirring at the same temperature for 3 hours, the reaction solution was concentrated and water was added to the residue.
Add 20 ml, saturate with sodium chloride and extract with chloroform. After washing with 10% sodium hydroxide, rinse with a small amount of water and dry. After distilling off the solvent,
The residue was purified with a silica gel column and recrystallized from ether to obtain 2 g of o-methoxycarbonyl-α-(1-piperazinyl)acetanilide in the form of colorless needles.
get. Melting point 94-96℃ Similarly, ο-(α-chloroacetylamino)
α-chloroacetanilide is used in place of benzoic acid methyl ester to obtain colorless amorphous crystals of α-(1-piperazinyl)acetanilide. Melting point 71-72
°C (THF-n-hexane) Example 1 6.5 g of o-methoxycarbonyl-α-(1-piperazinyl)acetanilide and 2.4 g of triethylamine were dissolved in 50 ml of methylene chloride, and 3,4-
A solution of 5.4 g of dimethoxybenzoyl chloride in methylene chloride is added dropwise while stirring while cooling with ice water. After reacting at the same temperature for 1 hour, the reaction solution was washed with water, a 5% aqueous sodium bicarbonate solution, and then a potassium carbonate aqueous solution.
dry. Methylene chloride is distilled off, and ethyl acetate is added to the acid residue to crystallize it. Recrystallization from ethanol yields colorless needle-shaped crystals of ο-methoxycarbonyl-α-[4-(3,4-dimethoxybenzoyl)
7.5 g of -1-piperazinyl]acetanilide are obtained. Melting point 167.5-169.0℃ Elemental analysis value (as C ₂₃ H ₂₇ O ₆ N ₃ ) C H N Calculated value (%) 62.57 6.16 9.52 Analysis value (%) 62.71 6.10 9.48 Example 2 p-methoxycarbonyl-α-(1 -piperazinyl)acetanilide 3.3 g and potassium carbonate 1.7
g was dissolved in 50 ml of DMF, and a methylene chloride solution of 2.7 g of 3,4-dimethoxybenzoyl chloride was added dropwise to the solution under ice-water cooling and stirring. React at the same temperature for 2 hours,
Furthermore, 100 ml of methylene chloride was added to the reaction solution, and the methylene chloride layer was mixed with water, 5% aqueous sodium hydrogen carbonate solution,
Next, it is washed with potassium carbonate water and dried. Methylene chloride was distilled off, and the residue was purified using a silica gel column to obtain p-methoxycarbonyl-α-[4-(3,
4-dimethoxybenzoyl)-1-piperazinyl]
3.3 g of acetanilide are obtained. Elemental analysis value (as C ₂₃ H ₂₇ O ₆ N ₃ ) C H N Calculated value (%) 62.57 6.16 9.52 Analysis value (%) 62.67 6.05 9.41 Colorless oil NMR; δ ^CDCl3 _ppn = 2.63 (m, 4H), 3.17 (s, 2H)
,
3.70 (m, 4H), 3.85 (s, 9H), 6.74~7.03
(m, 3H), 7.58 (d, J=8.5Hz, 2H),
7.97 (d, J = 8.5 Hz, 2H), 9.14 (brs, 1H) Example 3 3.3 g of 3,4-dimethoxybenzoic acid was dissolved in 30 ml of dimethylformamide, and triethylamine
Add 2.4g. 2.75 g of isobutyl chloroformate is added dropwise to the mixture while stirring and cooling with ice water, and the mixture is stirred for 30 minutes. A DMF solution of 4.6 g of α-(1-piperazinyl)acetanilide was added dropwise to the mixture while stirring at room temperature, and the mixture was stirred for 5 hours. The reaction solution was concentrated to dryness, chloroform,
Extract by adding 1N aqueous sodium hydroxide solution.
The chloroform layer was washed with water, dried, and then evaporated. The residue was dissolved in isopropanol, and hydrochloric acid-ethanol was added to obtain the hydrochloride. Recrystallization from ethanol gave α-[4-(3,4 2.3 g of -dimethoxybenzoyl)-1-piperazinyl]acetanilide monohydrochloride are obtained. Melting point 225-226°C Elemental analysis value (as C ₂₁ H ₂₅ O ₄ N ₃・HCl) C H N Calculated value (%) 60.07 6.24 10.01 Analysis value (%) 60.21 6.15 10.08 Example 4 Same as Examples 1 and 3 to obtain the following compound. Γ α-[4-(4-methoxybenzoyl)-1-
Piperazinyl]acetanilide monohydrochloride 1/
Dihydrate Colorless flaky crystals (ethanol) Melting point 241-244℃ (decomposed) Γ m-methoxycarbonyl-α-[4-(3,4
-dimethoxybenzoyl)-1-piperazinyl]
Acetanilide colorless oil NMR; δ ^CDCl3 _ppn = 2.63 (m, 4H), 3.17 (s, 2H)
,
3.70 (m, 4H), 3.86 (s, 6H), 3.88 (s,
3H), 6.73-7.03 (m, 3H), 7.33-7.46
(m, 1H), 7.66~7.82 (m, 1H), 7.90~
8.03 (m, 2H), 9.05 (s, 1H) Example 5 ο-(α-chloroacetylamino)benzoic acid methyl ester 10.06g, N-(3,4-dimethoxybenzoyl)piperazine monohydrochloride 15.2g and 16 g of triethylamine is suspended in 55 ml of acetonitrile and reacted at 49-50°C for 4 hours. After the reaction, cool with ice water and collect the precipitated crystals. This was recrystallized from ethanol to give colorless needle-like crystals of o-methoxycarbonyl-α-[4-(3,4-dimethoxybenzoyl)-
14.68 g of 1-piperazinyl]acetanilide are obtained. Melting point 167.5-169.0℃ Elemental analysis value (as C ₂₃ H ₂₄ O ₆ N ₃ ) C H N Calculated value (%) 62.57 6.16 9.52 Analysis value (%) 62.48 6.15 9.43 Example 6 m-(α-chloroacetylamino) 5 g of benzoic acid methyl ester, 7.56 g of N-(3,4-dimethoxybenzoyl)piperazine monohydrochloride, 7.76 g of triethylamine, and 30 ml of acetotrile in 45~
React at 50°C for 5 hours. The reaction solution was cooled with ice water and the precipitated crystals were removed. The mother liquor is concentrated to dryness and extracted with 1N aqueous sodium hydroxide solution and chloroform. The chloroform layer was washed with water, dried, and then evaporated, and the resulting oil was purified with a silica gel column to obtain 10.08 g of m-methoxycarbonyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide. . Elemental analysis value (as C ₂₃ H ₂₇ O ₆ N ₃ ) C H N Calculated value (%) 62.57 6.16 9.52 Analysis value (%) 62.42 6.23 9.61 Colorless oil NMR; δ ^CDCl3 _ppn = 2.63 (m, 4H), 3.17 (s, 2H)
,
3.70 (m, 4H), 3.86 (s, 6H), 3.88 (s,
3H), 6.73-7.03 (m, 3H), 7.33-7.46
(m, 1H), 7.66~7.82 (m, 1H), 7.90~
8.03 (m, 2H), 9.05 (s, 1H) Example 7 The following compound was obtained in the same manner as in Example 5. Γ α-[4-(4-methoxybenzoyl)-1-
Piperazinyl]acetanilide monohydrochloride 1/
Dihydrate Colorless flaky crystals (ethanol) Melting point 241-244℃ (decomposition) Γ α-[4-(3,4-dimethoxybenzoyl)
-1-piperazinyl]acetanilide monohydrochloride Colorless amorphous crystal (ethanol) Melting point 225-226℃ Γ ρ-methoxycarbonyl-α-[4-(3,4
-dimethoxybenzoyl)-1-piperazinyl]
Acetanilide colorless oil NMR; δ ^CDCl3 _ppn = 2.63 (m, 4H), 3.17 (s, 2H)
,
3.70 (m, 4H), 3.85 (s, 9H), 6.74~7.03
(m, 3H), 7.58 (d, J=8.5Hz2H), 7.97
(d, J = 8.5Hz, 2H), 9.14 (brs, 1H) Example 8 8.28g of potassium carbonate was mixed with water-acetone (1:2)
Dissolve in 50ml and add 9.3g of aniline. Under ice water cooling, [4-(3,4-dimethoxybenzoyl)-1
A solution of 34.4 g of -piperazinyl]acetyl chloride in acetone is added dropwise. After the dropwise addition, the mixture was reacted at room temperature for 3 hours, and the acetone was distilled off. This is extracted with chloroform, washed with water and dried, and then the chloroform is distilled off. The residue was dissolved in isopropanol, hydrochloric acid-ethanol was added to make the hydrochloride salt, and recrystallized from ethanol to obtain colorless amorphous crystals of α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide monohydrochloric acid. Obtain 29 g of salt. Melting point 225-226℃ Elemental analysis value (as C ₂₁ H ₂₅ O ₄ N ₃・HCl) C H N Calculated value (%) 60.07 6.24 10.01 Analysis value (%) 59.89 6.32 10.21 Example 9 [4-(4-methoxy) Dissolve 2.5 g of benzoyl-1-piperazinyl]acetic acid in 30 ml of DMF and add 1.2 g of triethylamine. 1.4 g of isobutyl chloroformate is added dropwise to the mixture while stirring and cooling with ice water, and the mixture is stirred for 30 minutes. Add 1 g of aniline to this while stirring at room temperature.
Add DMF solution dropwise and stir for 6 hours. The reaction solution was concentrated to dryness, and extracted with chloroform and 1N sodium hydroxide. The chloroform layer was washed with water, dried, and then evaporated, the residue was dissolved in isopropanol, and hydrochloric acid-ethanol was added to make the hydrochloride, which was then recrystallized from ethanol to obtain colorless scaly crystals of α-[4
-(4-methoxybenzoyl)-1-piperazinyl]acetanilide monohydrochloride 1/2 hydrate 2.1g
get. Melting point 241-244℃ (decomposed) Elemental analysis value (as C ₂₀ H ₂₃ O ₃ N ₃・HCl ・1/2H ₂ O) C H N Calculated value (%) 65.68 6.32 10.53 Analysis value (%) 65.72 6.31 10.40 Implementation Example 10 The following compound is obtained in the same manner as in Examples 8 and 9. Γ ο-methoxycarbonyl-α-[4-(3,4
-dimethoxybenzoyl)-1-piperazinyl]
Acetanilide Colorless needle crystals (ethanol) Melting point 167.5-169.0 Γ m-methoxycarbonyl-α-[4-(3,4
-dimethoxybenzoyl)-1-piperazinyl]
Acetanilide colorless oil NMR; δ ^CDCl3 _ppn = 2.63 (m, 4H), 3.17 (s, 2H)
,
3.70 (m, 4H), 3.86 (s, 6H), 3.88 (s,
3H), 6.73-7.03 (m, 3H), 7.33-7.46
(m, 1H), 7.66~7.82 (m, 1H), 7.90~
8.03 (m, 2H), 9.05 (s, 1H) Γ ρ-methoxycarbonyl-α-[4-(3,4
-dimethoxybenzoyl)-1-piperazinyl]
Acetanilide colorless oil NMR; δ ^CDCl3 _ppn = 2.63 (m, 4H), 3.17 (s, 2H)
,
3.70 (m, 4H), 3.85 (s, 9H), 6.74~7.03
(m, 3H), 7.58 (d, J=8.5Hz, 2H),
7.97 (d, J = 8.5Hz, 2H), 9.14 (brs, 1H) Formulation example 1 α-[4-(3,4-dimethoxybenzoyl)-
1-Piperazinyl]acetanilide monohydrochloride
5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets containing the above composition were prepared in a conventional manner. Formulation example 2 ο-methoxycarbonyl-α-[4-(3,4-
dimethoxybenzoyl)-1-piperazinyl]
Acetanilide 500mg polyethylene glycol (molecular weight: 4000)
0.3g Sodium chloride 0.9g Polyoxyethylene sorbitan monooleate
0.4g Sodium metabisulfite 0.1g Methyl-paraben 0.18g Propyl-paraben 0.02g Distilled water for injection 1000mg The above parabens, sodium metabisulfite and sodium chloride are dissolved in the above distilled water at 80°C with stirring. The resulting solution was cooled to 40°C, and the compound of the present invention, followed by polyethylene glycol and polyoxyethylene sorbitan monooleate, were dissolved in the solution. Next, distilled water for injection is added to the solution to adjust the final volume, and the solution is sterilized by sterilization using a suitable filter paper and dispensed into ampoules in 1 ml portions to prepare an injection.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom or a lower alkoxycarbonyl group, R ² represents a lower alkoxy group, A represents a lower alkylene group, and n represents 1 or 2, respectively. ] Aniline derivatives and salts thereof represented by: