JPS6133027B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula () piperazine derivatives thereof, their pharmaceutically acceptable organic and inorganic salts, and their preparation. The new compound with the experimental abbreviation S1429 can be given the following chemical name: N-2-(3-benzezoylphenyl)-propionylethylenedioxyethyl-N'-(4-chlorobenzhydryl)
-Piperazine This compound, an organic substance with two basic functional groups, can be salted with both inorganic and organic acids and forms mono- and di-salts with each. If organic or inorganic acids with two acid functions are used, acidic as well as neutral salts are obtained. Novel piperazine derivatives of formula () are 2-(3-benzoylphenyl)-propionic acid of formula () and N-(4-chlorobenzhydryl)-N'-2-(2- hydroxyethoxy)-
It can be obtained from ethyl-piperazine by a method of forming an ester bond according to the general reaction described below. This method is as follows: (A) The acid of formula () is converted to the corresponding formula (). (wherein X is chlorine, bromine, iodine or fluorine) and reacting the latter with a piperazine alcohol of formula (). This reaction can be carried out in an inert anhydrous organic solvent both in the presence and absence of an organic or inorganic base. (B) Corresponding formula () for the acid in formula () Formula and this product of formula () is reacted with an alcohol of formula () either in the presence or absence of an inert anhydrous organic solvent. (C) General formula () corresponding to the acid of formula () Formula (wherein R can be alkyl, aryl or cycloalkyl) and then convert the compound of formula () into a piperazine alcohol of formula () in a suitable inert anhydrous organic solvent. react with. (D) Approximately equimolar amounts of an acid of formula () and an alcohol of formula () are prepared in an inert anhydrous organic solvent by the general formula () R-N=C=N-R' () where R and R' may be the same or different and each can be alkyl, aryl or cycloalkyl [these are described in the literature (A. Busar and co-workers, "CRAcad.Sc." 256 , 1804
(1963); Neelakuntar and co-workers, Tetrahedron 21 , 3531 (1965)). (E) Approximately equimolar amounts of an acid of formula () and an alcohol of formula () are subjected to RC using trifluoroacetic anhydride as the esterifying agent, either in the presence or absence of an inert anhydrous organic solvent.
Parish and co-researcher's "Tetrahedron left."
1964, 1258 and “J.Org.Chem.” 30 , 927
(1965). (F) An acid of formula () dissolved in anhydrous pyridine is reacted with benzenesulfonyl or p-toluenesulfonyl halide, and to this mixture an alcohol of formula () is added in an equitolary amount as an acid of formula () to prepare the JHBrewster and CJCiotti , “J.Am.
Chem. Soc. 77 , 6214 (1955). (G) K.Saigo and joint research institute “Bull.Chem.Soc.
Japan” 50 , 1863 (1977) and T.Mukaiyama
and co-researcher "Chem. Lett." 1975,
1045:1976, an inert solvent of either 2-bromo-1-methylpyridinium iodide or 2-bromo-1-methylpyridium tetrafluoroborate by applying the method for obtaining the ester described in 13. The acid of formula () and the alcohol of formula () dissolved in an organic solvent are added to the suspension in approximately equimolar amounts and reacted. (H) An ester of formula () is a salt of an acid of formula () or a derivative of an alcohol of formula (). (wherein X is halogen, preferably chlorine or bromine). This is British Patent No. 1174819 and French Patent No.
It can also be obtained as described in No. 73.03599. (I) Finally, the ester corresponding to formula () is formula () (wherein X is halogen), i.e. 2-halogenethyleneoxyethyl-2'-
2-(3-benzoylphenyl)-propionate of ol is expressed by the formula (). It can also be obtained by reacting with p-chlorobenzhydrylpiperazine. The compounds of formula () and their organic and inorganic salts are suitable for biological and clinical applications and exhibit important pharmacodynamic activities in both animals and humans, namely anti-inflammatory, antipyretic, analgesic, anti-diffusive, muscle relaxing and anti-inflammatory activities. Indicates histamine action. The active dose in pharmacological experiments is 3-60 according to tests.
mg/Kg/os, while the maximum tolerated dose is
250−1000mg/Kg/os. Due to its unique pharmacological activity and its low toxicity, this product has a very favorable therapeutic index, which makes it easy to handle, especially when compared with drugs of the same category already used in clinical applications. , and is well tolerated. It has also been found that the products of formula () exhibit very little of the secondary phenomena normally observed in the drug category to which it belongs, such as fluid retention and irritation of the gastrointestinal tract. This organic compound, object of the present invention, finds application in all arthritic and myositis conditions for which anti-inflammatory substances are conventionally prescribed. Pharmacodynamic activity was observed to be similar qualitatively and quantitatively when the drug was administered either orally, rectally, or parenterally. According to the present invention, the products of formula () are therapeutically applicable both as diluent bases and as pharmaceutically acceptable salts. Pharmaceutical compositions comprising the product of formula () and/or its pharmaceutically acceptable salts, both as pure products and in the presence of diluents or coating agents, are also objects of the present invention. . Such pharmaceutical compositions can be used by oral, rectal or parenteral methods or in ointments/pomades. According to the present invention, tablets, powders or granules can be used as solid pharmaceutical compositions. In said pharmaceutical compositions, the active product according to the invention is mixed with an inert diluent such as sucrose, lactose or starch, and substances other than diluents, for example lubricants such as magnesium stearate, are present. May exist. According to the invention, as a liquid pharmaceutical composition for oral administration, a pharmaceutically acceptable emulsion comprising an inert diluent such as water or paraffin oil;
Solutions, suspensions, syrups and elixirs are used. Besides the diluent, the pharmaceutical dosage form may also contain other substances, such as emulsifying, coloring or perfuming substances. Further according to the invention, pharmaceutical compositions for parenteral application may be either aqueous or non-aqueous, sterile, solution suspensions or emulsions. As solvents or vehicles, for example propylene glycol, polyethylene glycol, vegetable oils such as olive oil and/or injectable organic esters such as ethyl oleate can be used. The pharmaceutical composition may optionally contain emulsifying agents and dispersing agents. Sterilization can be carried out in various ways: for example, either by means of a bacterial sieve or by incorporating a sterilizing agent into the composition or by irradiation or heating. Injectable pharmaceutical forms may be prepared as sterile solid pharmaceutical compositions and dissolved in sterile injectable liquid at the time of use. Pharmaceutical compositions of the invention for rectal administration are in the form of suppositories which, in addition to the active product, contain excipients such as cocoa butter, or suitable waxes for suppositories. The dosage of the compound of formula () and/or the pharmaceutically acceptable salt used according to the invention depends on the desired therapeutic effect, the method of administration and the duration of treatment. A daily dose of 350 mg to 750 mg can be used in clinical medicine. 2-(3-Benzoylphenyl)-propionic acid of formula (), which is an intermediate for obtaining the compound of formula (), is disclosed in British Patent No. 1164585 and French Patent No.
6.444M and as described in South African Patent No. 6804682. The above formula ()
The acid can also be obtained by other synthetic methods: Reference A (E. Ador, AARilliert - "Ber." 12 ,
2298, 1879), 3-bromomethylbenzophenone is obtained by treatment with N-bromosuccinimide, and cyanation from this latter material. 3-Benzoylphenylacetonitrile is obtained by treatment with sodium or potassium. 2-(3-Benzoylphenyl)-propionic acid is obtained from this nitrile in various ways: H. Normont and B. Angelo with sodium hydride and iodomethane.
(“Bull Soc. Chim. France” 1962, 810; 1961,
(1988; 1960, 354) for the latter case, followed by saponification of the nitrile, or the 3-benzoylphenylacetonitrile is dissolved all at once in 3-benzoylphenyl acetic acid. saponified and the above-mentioned
It is obtained by α-methylation of this sodium salt in the same manner as mentioned by Normont and Angelo. Finally, 3-benzoylphenyl acetic acid is converted to the corresponding ethyl ester and α-methylated with sodium hydride and iodomethane to yield ethyl 2-(3-benzoylphenyl)propionate, from which it is simply saponified. An acid of formula () is obtained. This manufacturing process is shown in Table 1. B is a known compound, and HESmith has published [“J.Am.
Chem.Soc.'' 43 , 1920-1921, Azndt-
Eistert's synthesis method ("Organic react." vol. I, 38
Page 1942; Weygand, Bestmann - “Angew.
Chem. 72 , 535-1960: describes a general method for increasing the number of carbon atoms in an organic acid chain)
Starting from 3-benzoylbenzoic acid prepared [by], 2-benzoyl-phenylacetic acid is obtained and from this the acid of formula () is prepared by the conventional α-methylation process already described in A above. Get it. Otherwise, however, it is easier to
ALWilds and ALMeader (“J.Org.Chem.”
13 , 764-1948) and K. Balenovic and I.
By applying the procedure of Jambresie ("Chem.Ind." 1955, 1673), we again chain-extend the acid from 3-benzoylbenzoic acid and simultaneously α-methylate the acid of formula (). get. The manufacturing process diagram is shown in Table 2. Another procedure available for the synthesis of acids of formula (C) is by PRJones and IRYoung ("J.Org.Chem."
33 , 1675-2968). Dilthey (“J.Prak.Chem.” 109 [2], 318)
In 1925, Montagne ("Rec. Trav. Chim."
Starting from 3-bromobenzophenone, a product obtained by Paesi Bassi-42.607) in 1923, the corresponding Grignard compounds are obtained by conventional magnesium reactions. From this, 3-benzoylphenyl cadmium chloride is obtained by the Jones and Young procedure described above, which is converted into 2-(3-benzoylphenyl)-propionic acid by reaction with ethyl α-halogenpyropionic acid. When ethyl is produced and this is saponified in either an acidic or basic environment, an acid of formula () is reached. This manufacturing process is shown in Table 3. Preparation of 2-(3-benzoylphenyl)-propionic acid (A) from m-methylbenzophenone Step 1 3-Bromomethylbenzophenone E. Adar, AARilliert ("Ber." 12, 2298-
The boiling point obtained as described by (1879) is 127−
130° (1 mm) of m-methinebenzophenone (19.6 g: 0.1 mol) is dissolved in an inert anhydrous solvent such as chloroform or carbon tetrachloride and in an inert atmosphere is dissolved with N-bromosuccinimide (19.6 g: 0.1 mole). :0.11 mol) and a catalytic amount of dibenzoyl peroxide (0.5-1 g).
This mixture was then subjected to TLC (Thin Layer Chromatography) test (sheet Merck) under reflux.
Heating is allowed to proceed for several hours until F254-ethyl acetate) indicates completion of the reaction. A sufficient amount of sodium iodide dissolved in acetone is carefully added to decompose the dibenzoyl peroxide, the reaction medium is then filtered and the liquor is evaporated to dryness. Dissolve the residue in carbon tetrachloride,
Carefully dissolve and filter, and repeat the above operation to completely separate the succinimide. If necessary, the last traces of this product can be removed by a short column of silica gel chromatography, eluting first with carbon tetrachloride and later with chloroform. The purified liquid is dried and evaporated to completely remove the solvent, leaving an oil as a residue. This solidifies when cooled and rubbed. The 3-bromomethylbenzophenone thus obtained can be crystallized from chloroform/petroleum ether. melting point 69
−71°C (uncorrected) Step 2 3-Benzoylphenylacetonitrile 3-bromomethylbenzophenone (13.75 g, 0.05 mol) dissolved in ethanol was mixed with potassium cyanide (3.6 g, 0.055 mol) or sodium cyanide (2.7 g, 0.055 mol) in an aqueous solution. The mixture is refluxed for 8 to 16 hours and finally evaporated under reduced pressure. The residue thus obtained was vacuum distilled and 208−
The fraction passing through at 215°C (1 mm) is collected. This gives 3-benzoylphenylacetonitrile in the form of an oil which is sufficiently purified for the next step. Step 3 3-Benzoylphenylacetonitrile to 2-(3-benzoylphenyl)-propionic acid (with sodium naphthalene and iodomethane) H. Normont, B. Angelo (“Bull.Soc.Chem.
France” 1962, 810; 1961, 1988; 1960,
To a solution of sodium naphthalene (0.066 mol) in anhydrous tetrahydrofuran was added 3-benzoylphenylacetonitrile (6.65 g,
0.03 mol) solution. A slight temperature rise occurs during the addition. The mixture is stirred for 2.5 hours and then cooled in an ice-salt bath. At this time, iodomethane diluted with diethyl ether (4.25 g:
1.9 ml; 0.03 mol) is added dropwise. This addition takes 45 to 60 minutes to maintain the temperature at about 0°C. The reaction liquid is allowed to rise to room temperature, then diethyl ether and an equal amount of water are added. The alkaline layer is separated and extracted with ether, then the synthesized ether layer is washed with water, dried and evaporated. This residue is dissolved in a solution of sodium or potassium hydroxide in alcohol-water and boiled under reflux for 8 to 15 hours.
After cooling, more water is added and the alkaline solution is then washed with an immiscible organic solvent such as dichloromethane, filtered, cooled and made highly acidic with a mineral acid, for example sulfuric acid. At this time a solid precipitates out (if an oil precipitates, it is extracted with a solvent, dried and evaporated) and after two crystallizations from benzene-petroleum ether, the purified 2-
(3-Benzoylphenyl)-propionic acid (mp 92-95°C (uncorrected)) is produced. The melting point does not decrease when mixed with a reference sample of this acid. Step 4 3-Benzoylphenylacetonitrile to 2-(3-benzoylphenyl)-propionic acid (with sodium hydride and iodomethane) Proceed as in the previous preparation except that sodium naphthalene is replaced with sodium hydride. and similar operation in a suitable inert anhydrous solvent such as benzene or toluene in addition to tetrahydrofuran gives the same acid, but in a lower yield. Step 5 3-Benzoylphenylacetonitrile to 3-benzoylphenyl acetic acid 3-Benzoylphenylacetonitrile (22.1 g, 0.1 mole) is boiled and refluxed with a mixture of equal volumes of sulfuric acid, acetic acid and water for about 2 to 4 hours. After cooling, the reaction mixture was diluted with water to complete the production of 3-benzoylphenyl acetic acid, with a melting point of 111-114°C (uncorrected). Step 6 From 3-benzoylphenylacetic acid to 2-
(3-Benzoylphenyl)-propionic acid (with sodium naphthalene and iodomethane) Sodium salt of 3-benzoylphenyl acetic acid by treating 3-benzoylphenyl acetic acid with one equivalent of sodium hydroxide or sodium alkoxide. Convert to This purified sodium 3-benzoylphenylacetate has a melting point of 146-148°C (uncorrected) and is dissolved in sodium naphthalene (0.1 mol) in anhydrous tetrahydrofuran (13.1 g, 0.05 mol) in anhydrous tetrahydrofuran. ) to the solution. After stirring for 2 to 5 hours, the mixture is cooled and iodomethane (7.1 g, 0.05 mole) dissolved in anhydrous diethyl ether is slowly added dropwise while maintaining the temperature of the reaction liquid at about 0°C. . Allow the temperature to rise to room temperature, then add more diethyl ether and water. Separate this alkaline layer, wash with ether,
Cooled and highly acidified with dilute mineral acid, thereby precipitating 2-(3-benzoylphenyl)-propionic acid, which was recovered, washed, and recrystallized from benzene-petroleum ether. do. The melting point is 94-95°C, consistent with that previously mentioned. Step 7 Ethyl 2-(3-benzoylphenyl)propionate (3-benzoylphenyl acetic acid) 3-benzoylphenyl acetic acid (7.2 g, 0.03 mol) is added and the mixture is boiled under reflux for several hours. After evaporating the ethanol under reduced pressure, the residue is dissolved in water and chloroform, the layers are separated and the organic layer is washed with a dilute alkaline solution, for example aqueous sodium hydroxide solution, dried and evaporated. The residue was dissolved in an inert organic solvent, preferably anhydrous tetrahydrofuran, air was purged from the apparatus with nitrogen, and the solution was dissolved in either sodium hydride or sodium hydride (0.02 mol) suspended in paraffin. Process with. The mixture is heated with stirring in an inert atmosphere for 2 to 5 hours, taking care to avoid hydrogen evolution. After cooling, iodomethane is added while maintaining the temperature at approximately 0°C. At the end of the addition, the mixture is stirred for several hours and allowed to rise to room temperature. Add a small amount of ethanol to destroy excess sodium hydride and then evaporate the solvent. Dissolve this residue in dichloromethane. The organic solution was washed with alkali diluted with brine, dried, evaporated and finally the residue was distilled under reduced pressure to give ethyl 2-(3-benzoylphenyl)propionate (boiling point 160-162
℃ (0.2mm)). Step 8 2-(3-benzoylphenyl)-propionic acid (2-(3-benzoylphenyl)-
ethyl ester of 2-(3-benzoylphenyl)-propionic acid (from ethyl propionate) in an alkaline environment (e.g. hydro-alcoholic solution of sodium hydroxide).
and in acidic environments (e.g. hydrochloric acid in hydro-acetic acid). In both cases, the same acid obtained in the above procedure is obtained with a melting point of 94-95°C. (B) From 3-benzoylbenzoic acid HESmith ("J.Am.Chem.Soc." 43, 1920-
3-benzoylbenzoic acid (2.26 g; 0.01 mol), obtained as described by (1921), was added until no further hydrochloric acid fumes were produced (2 to 6 hours).
Treat with thionyl chloride (10 ml excess) and then heat the mixture to 40-60°C for approximately 1 hour. Excess thionyl chloride is removed under reduced pressure, the residue is dissolved in anhydrous benzene and evaporated again under reduced pressure. The acid chloride was dissolved in anhydrous diethyl ether and the solution was mixed with diazoethane (0.22 mol) [as prepared by Worlds and coworkers (J.Org.Chem., 13, 753, 1948)]. Add dropwise to another ether solution containing precooled to -20°C. This addition was carried out for approximately 1 hour,
Excess diazoethane then lowers this temperature to -
Remove under vacuum while keeping at 20℃. When the compound is completely removed (this can be noticed as the solution becomes colorless), the remaining solvent is reduced to approximately 0.
℃ to obtain a solid residue, which was repeatedly dissolved in cold petroleum ether. The aforementioned diazoketone (1.0 g) dissolved in a mixture of equal volumes of anhydrous benzyl alcohol and anhydrous collidine is placed in a flask equipped with a reflux condenser and protected against moisture. The flask is immersed in a bath preheated to 170 DEG-190 DEG C., which causes significant nitrogen evolution after 2-3 seconds, but this ends in 5 to 15 minutes. The reaction mixture is cooled, then ether is added and the ether solution is washed with dilute hydrochloric acid. After drying and evaporation, 2-(3-
The benzyl ester of (benzoylphenyl)-propionic acid is obtained, which is hydrolyzed with a mixture of equal volumes of methanol and potassium hydroxide in 45% water. The methanol is evaporated off under reduced pressure, water is added and, after cooling, 2-(3-benzoylphenyl)-propionic acid is precipitated by acidification with mineral acid. This product is collected, washed and recrystallized to provide a purified acid with the same characteristics as obtained above. In the same way, diazoethane is replaced with diazomethane to give 3-benzoylphenyl acetic acid, which can be converted into 2-(3-benzoylphenyl) by one of the methods already described (Steps A 6, 7 and 8). - Can be converted to propionic acid. (C) From 3-bromobenzophenone Dilthey ("J.Prak.Schem." 109(2), 318-
3-bromobenzophenone (13.1 g; 0.05 mol), obtained as described by (1925), was reacted with the halide in a conventional Grignard reaction in the presence of two iodine crystals in anhydrous tetrahydrofuran. It is converted to benzophenone-magnesium-bromide by treatment with molar amounts of magnesium chips. After boiling the solution for 30 minutes, strain to remove any excess magnesium, if present.
To this solution, which has been cooled to room temperature, an equimolar amount of anhydrous cadmium chloride is added with cooling over a period of about 15 minutes. At the end of the addition, the Gilman test ("J.Am.
Chem.Soc.) 47, 2002-1925), the disappearance of the Grignard reagent is observed. In a tetrahydrofuran solution containing reactive benzophenone-3-cadmium chloride, 2
-Ethyl bromopropionate (4.53g; 0.025
mol). The mixture is heated slightly to make it more fluid, and 3N hydrochloric acid is added after about 8 hours. The solvent is almost completely evaporated and the concentrate is dissolved in an organic solvent such as dichloromethane and water. Separate the organic layer, add dilute alkali,
Washing with water, dilute acid and water again, finally drying and evaporation gives an oil as a residue, which is fractionally distilled under reduced pressure to give 2-(3-benzoylphenyl)-
Ethyl propionate (boiling point 160-162℃ (0.2
mm)). From now on, step A 6 and 7
The corresponding acids with melting points of 94-95° C. are obtained by saponification as described in 8 and 8. The examples described below are intended to illustrate the invention and are not intended to limit its scope. Example 1 In a flask equipped with a stirrer and reflux condenser, 2-(3-benzoylphenyl)-propionic acid (13.71 g; 0.05 mol) was reacted with excess thionyl chloride in the presence of anhydrous diethyl ether.
The mixture was boiled for 6 hours while stirring, then the solvent and excess thionyl chloride were evaporated under reduced pressure. The residue was then dissolved in anhydrous benzene and evaporated again to dryness. Repeat this process,
This leaves a slightly yellow oil of 2-(3-
Benzoylphenyl)-propionyl chloride was obtained, which was used directly in the next preparation. N-(4-chlorobenzhydryl)-N'-(hydroxyethoxyethyl)piperazine base (18.75 g; 0.05 mol) was inactivated in a flask equipped with a stirrer, reflux condenser, and protected from moisture. of anhydrous solvents, benzene and toluene. To this solution was added all the acid chloride prepared above dissolved in the same solvent, and then the mixture was boiled for 4 hours. After cooling to room temperature, the reaction liquid was washed with saturated aqueous sodium bicarbonate solution and then with water. The separated, dried and filtered organic layer was cooled and a stream of gaseous hydrochloric acid was bubbled through while still cooling and stirring. A white precipitate thus formed, which was filtered and washed on the filter with anhydrous diethyl ether. After drying, the slightly hygroscopic product crystallizes,
Analytically pure N-[2-(3-benzoylphenyl)propionylethylenedioxy-ethyl]-
N'-(4-chlorobenzhydryl)-piperazine dihydrochloride (melting point 86-93°C (uncorrected)) was produced (yield 68%). Analysis of C ₃₇ H ₉₉ ClN ₂ O _4.2HCl HCl Calculated % 10.66 Measured % 10.56 Instead of anhydrous diethyl ether, other low boiling inert solvents such as anhydrous dichloromethane can also be used. Example 2 In a suspension of N-(4-chlorobenzhydryl)-N'-(hydroxyethoxyethyl)-piperazine dihydrochloride (22.4 g; 0.05 mol) in toluene,
Anhydrous triethylamine (15.2 g) was added with cooling. To this mixture was added 2-(3-benzoylphenyl)-propionyl chloride (13.6 g; 0.05 mol) prepared as described in Example 1 and diluted with toluene. The reaction mixture was boiled with stirring for 5 hours, then allowed to cool to room temperature and filtered to remove any solids present. The clear liquid was dried and evaporated to leave a pale yellow oil as a residue, which was soluble in ethanol. This alcoholic solution was then treated with an excess of saturated picric acid solution in ethanol with stirring. A yellow solid precipitated, which was collected on a Buchner filter after standing for several hours, washed with a small amount of ethanol, dried, and recrystallized from ethanol. N-[2-(3-benzoylphenyl)-propionylethylenedioxyethyl]-N'-(4-chlorobenzhydryl)-piperazine dipicrate (melting point 144-146°C (uncorrected)) was obtained. (yield 70
%). Analysis of C ₄₉ H ₄₅ ClN ₈ O ₁₀ C H N Calculated % 55.03 4.24 10.47 Measured % 55.20 4.33 10.32 Example 3 2-(3-Benzoylphenyl)-propionic acid was treated as in Example 1. However, thionyl bromide was used instead of thionyl chloride as the halogenating reagent. 2-(3-
Benzoyl phenyl)-propionyl bromide was obtained as a yellow-orange oil. This was reacted as in Example 1 with N-(4-chlorobenzhydryl)-N'-(hydroxyethoxyethyl)-piperazine. After carrying out the usual work-up described in Example 2, the crude N-[ ^2- (3- _{benzoylphenyl} )-propionyl ethylene dioxyethyl)]-N'-( 4-chlorobenzhydryl)-
The free base of piperazine was obtained which was purified by a silica gel column and an analytical sample was obtained using chloroform or ethyl acetate as eluent (66% yield). Thin layer chromatography: Silica gel sheet (Merck F254) Ethyl acetate solvent: Unit spot Rf0.33 Analysis of C ₃₇ H ₃₉ ClN ₂ O ₄ C H N Calculated value % 72.71 6.43 4.58 Measured value % 72.83 6.40 4.61 This base is The spectrum (10γ/ml in ethanol) shows λ255μm (E ¹ % ₁ cm282) and λ230μ
Two absorption maxima appear at m (E ¹ % ₁ cm 355) and in the IR spectrum 2800; 1740;
Peaks appeared at 1665; 1600; 1490; 1455 and 1290 cm ^-1 . Example 4 2-(3-Benzoylphenyl)-propionic acid (25.42 g; 0.1 mol) was boiled with acetic anhydride (60-100 ml) for 12 hours. The excess anhydride and the resulting acetic acid were evaporated under reduced pressure, and the oily residue was dissolved in benzene, then the organic solution was washed with an 8% aqueous solution of sodium hydroxide, then with water, and after drying this organic layer. , this was evaporated, the residue was dissolved in ethanol and the alcoholic solution was kept in the cold for a very long time. The desired anhydride crystallized and was subjected to thin layer chromatography testing and still contained trace amounts of the starting acid. This crystallization was repeated until a chromatographically pure product was obtained. 2-(3-Benzoylphenyl)-propionic anhydride had a melting point of 213-216°C (uncorrected). To a solution of N-(4-chlorobenzhydryl)-N'-(hydroxyethoxyethyl)piperazine base (18.75 g; 0.05 mol) in benzene was added the previously prepared anhydride (27.0 g; 0.05 mol), The reaction mixture was then boiled for 2 to 8 hours. After cooling to room temperature, this organic solution was
% aqueous sodium hydroxide solution, 2-(3-
This aqueous alkaline layer from which benzoyl phenyl)-propionic acid can be recovered is removed, the organic layer is anhydrified, and the solvent is filtered and evaporated under reduced pressure to produce an oil as a residue, which is Dissolved in ethanol. The ethanolic solution was then cooled and cold concentrated sulfuric acid was slowly added with stirring. When the mixture became acidic, it was stirred while still cooling until the salt began to crystallize. After standing overnight in the cold, the solids were collected, washed on a filter with cold absolute ethanol, and dried under vacuum at 50-60°C. The crude product thus obtained was purified by crystallization from ethyl acetate. The analytically pure salt has a melting point of 147-150°C and is N-[2-(3-benzoylphenyl)
-propionylethylenedioxyethyl]-N'-
It was a disulfate salt of (4-chlorobenzhydryl)-piperazine (yield 57%).

[Table] Example 5 In a flask equipped with a stirrer, a charging funnel, a thermometer and a reflux condenser, thoroughly dried and protected against moisture, 2-(3-benzoylphenyl)-propionic acid ( 30.5 g; 0.12 mol) was dissolved in dimethyl ketone. To this solution was added anhydrous triethylamine (16.7 g; 0.12 mol). The mixture was cooled to between 0 DEG and -10 DEG C. and then ethyl chlorocarbonate (11.5 ml; 0.12 mol) was added with gentle stirring while maintaining the temperature between 0 DEG and 10 DEG C. Stirring was continued for 30 minutes at approximately -5°C, during which time a solid triethylamine hydrochloride precipitated in the reaction liquid, while at the same time a mixed anhydride of formula (R=C ₂ H ₅ ) was added to the solution. generated. Next, N-(4-chlorobenzhydryl)-N'-[2-(2-hydroxyethoxy)ethyl]piperazine base (37.5 g;
0.1 mol) was quickly added. Then reduce the temperature to 0℃
The reaction liquid was stirred for 30 minutes while keeping the temperature between -10 DEG C. and -10 DEG C., then the temperature was allowed to rise to room temperature and finally the mixture was stirred for 1 to 4 hours. The solids present were filtered off, washed on the filter with the ketone already used, and the liquor and washings were combined and evaporated. The residue was dissolved in ethyl acetate and the organic solution was washed with 5% aqueous sodium carbonate. The organic layer was separated, dried, and a filtered solution of maleic acid (25.5
g; 0.22 mol) was added. The mixture was stirred and the solution was carefully crystallized in the cold, protected against moisture. The product was collected and crystallized from ethyl acetate until the melting point was constant. A dimaleate salt with a melting point of 97-99° C. was thus obtained from the organic base of formula (54% yield).

[Table] Example 6 By using the same amounts and the same procedure as in Example 5, but replacing ethyl chlorocarbonate with isobutyl chloroformate (16.4 g; 0.12 mol),
The same product as in the previous example was obtained. However, the reaction efficiency was improved. After conventional work-up, the ester of formula () was obtained as the free base and purified on a silica gel column, eluting with ethyl acetate. The ester had the same refractive index as the ester obtained according to Example 3 and showed one chromatographic spot (yield 60%). Example 7 2-(3-benzoylphenyl)-propionic acid (5.1 g; 0.02 mol) and N-(chlorobenzhydryl)-N'-[2
A mixture of -(2-hydroxyethoxy)-ethyl]-piperazine (7.5 g; 0.02 mol) was treated with dicyclohexylcarbodiimide (4.5 g; 0.022 mol) and the thoroughly mixed mixture was stirred for an extended period of time with intermittent stirring. It was left at 40-80°C. The precipitated dicyclohexylurea was filtered off and the liquor was evaporated under reduced pressure (a second run was sometimes required to remove more dicyclohexylurea when half concentrated). The residue was dissolved in chloroform and the chloroform solution was washed first with water, then with dilute alkali and finally with water again. This solution was dried and evaporated, thus giving an oil as a residue which, when treated with picric acid as in Example 2, produced a salt with the same melting point, i.e. 144-146°C (mixed with melting point 144-146°C) (45% yield). Example 8 Dicyclohexyl-carbodiimide is converted to diisopropylcarbodiimide [(formula ()) (R=R'=
( _CH3 ) ₂ -CH-; boiling point 147-149)] and the procedure of Example 7 was carried out. After conventional treatment to obtain the free base of formula () as described in Examples 3 and 6,
The resulting oil was heated with an equimolar amount of maleic acid using ethyl acetate as the solvent for both base and acid. After standing in the cold for several hours, a white crystalline solid precipitated by rubbing, which was collected on a filter, washed with cold anhydrous ethyl acetate, and crystallized from anhydrous ethyl acetate. N
-[2-(3-Benzoylphenyl)-propionylethylene-diokidiethyl]-N'-(4-chlorobenzdolyl)piperazine monomaleate or neutral maleate salt (melting point 101-104℃)
(uncorrected)) was thus obtained (42% yield). Analysis of C ₄₁ H ₄₃ ClN ₂ O ₈ N Cl Calculated % 3.85 4.87 Measured % 3.73 4.80 Example 9 2-
(3-Benzoylphenyl)propionic acid (7.6
g, 0.03 mol) was dissolved in benzene. Trifluoroacetic anhydride (17ml) was added to this solution. After stirring for several minutes, the anhydrous base N-(4-chlorobenzhydryl)-N'-[2-(2-hydroxyethoxy)ethyl]-piperazine was added. The reaction mixture was kept at 20-60°C for several hours and then a 10% aqueous solution of sodium hydroxide was added. The organic layer was separated, washed with water, and then dried. This was filtered and evaporated to yield a yellowish oil as a residue, which was converted to dimaleic acid hydrochloride as described in Example 5. The salt obtained has the same melting point as Example 5
It showed the same chromatographic unit spot as the known sample (yield 51%). Example 10 The same procedure as in the previous example was carried out except for the solvent. Also in this example, the base obtained by conventional treatment was converted to the dimaleate salt, thus obtaining a compound with the same chemical-physical properties as obtained by Examples 5 and 8 (yield 38%). . Example 11 2-(3-benzoylphenyl)-propionic acid (12.7 g; 0.05 mol) was dissolved in anhydrous pyridine. Benzenesulfonyl chloride (17.5-26.5 g) was added to this solution, then the mixture was cooled from the outside in an ice bath, and when the temperature reached its minimum, N-(4-
chlorobenzhydryl)-N′-[2-(2-hydroxyethoxy)-ethyl]-piperazine (18.7 g;
0.05 mol) was added. After continuing to cool for 1 hour, the reaction liquid was poured into 3 to 4 times the volume of water, and the resulting mixture was heated to remove the pyridine-water azeotrope (boiling point 92-93°C (760 mm)). evaporated under reduced pressure. When the azeotrope could no longer be removed, the residue was dissolved in dichloromethane and the solution was washed with dilute alkali, such as 5% aqueous sodium hydroxide, and then with water. After drying, filtering and evaporating the organic layer, the base obtained was salified with sulfuric acid as described in Example 4 (53% yield). There was no difference in the melting points obtained by the two methods, and there was also no difference in the mixture (melting point 147-150°C (uncorrected)). Example 12 Worked as in Example 11 substituting p-toluenesulfonyl chloride for benzenesulfonyl chloride. The resulting disulfate had the same physical properties as those obtained by the procedures described in Examples 4 and 11 (58% yield). Example 13 In a flask equipped with a stirrer, a thermometer, and a gas inlet tube, 2-bromo-
1-Ethyl-pyridinium tetrafluoroborate (3.29 g; 0.012 mol) was dissolved. After removing all air from the interior of the apparatus by a slow flush of anhydrous nitrogen, while still maintaining this inert atmosphere,
-(3-Benzoylphenyl)-propionic acid (2.54 g; 0.01 mol), N-(4-chlorobenzhydryl)-N'-[2-(2-hydroxyethoxy)
A mixture of ethyl]-piperazine (3.74 g; 0.01 mole) and tributylamine (4.44 g; 0.024 mole) was added. After stirring overnight at room temperature, the solvent was evaporated and purified as described in Example 3 (yield 28
%). The product obtained as an almost colorless oil had the same physico-chemical and chromatographic properties as the free base obtained in the procedures of Examples 3 and 6. Example 14 The product was obtained in the same manner as in Example 13 above, except that 2-bromo-1-ethyl-pyridinium tetrafluoroborate was replaced by 2-bromo-1-methyl-pyridinium bromide. This latter reactant was tested by K. Saigo, M. Usui, K. Kikudri, E.
Shimada, T.Mukaiyama “Bull.Chem.Soc.
Jpn.'' 50/7, 1863 (1977) (yield 32%). Example 15 Potassium hydroxide (0.57 g; 0.01 mol) in distilled water
melted. To this solution was added 2-(3-benzoylphenyl)-propionic acid (2.54 g; 0.01 mole), which all dissolved in a short time. Separately, silver nitrate (1.52 g; 0.009 mol) was dissolved in distilled water.
With vigorous stirring, this silver nitrate solution was added to the solution containing the potassium salt of the acid. Silver 2-(3-benzoylphenyl)-propionate precipitated as a white solid, which was collected on a filter, washed with water, and then with a small amount of methanol. The salt was dried over phosphoric anhydride in the dark at room temperature under reduced pressure. All the salts obtained above are converted into intermediate N-(4
-chlorobenzhydryl)-N'-(2-bromoethoxyethyl)-piperazine (X=Br; obtained as described in British Patent No. 1174819 and French Patent No. 7303599) and stirred. Heat for several hours in a boiling water bath. The reaction mixture was dissolved in a 10% aqueous sodium hydroxide solution, and the whole was stirred and then extracted with chloroform.
This chloroform solution was washed with dilute aqueous alkali and water and then washed with a short Florisil column (Florisil column).
column) and finally examples 3, 6, and
The formula () by the silica gel column reported in 12
The pure ester of was obtained (47% yield). The resulting oil, when salted with sulfuric acid as reported in Example 4, melts at 147-150°C (uncorrected) both alone and in admixture with the product obtained in the procedure of Example 4. Sulfate was produced. Example 16 2-(3-Benzoylphenyl)-propionic acid (12.7 g; 0.05 mol) was converted to the corresponding acid chloride as described in Example 1. All of the 2-(3-benzoylphenyl)-propionyl chloride obtained was dissolved in benzene and an equimolar amount of (2-hydroxyethyl ether) (5.3 g; 0.05 mol) was added in the presence of triethylamine (0.055 mol). ) was reacted. The reaction mixture was boiled for several hours, then cooled, washed with 5% aqueous sodium carbonate, water, 2N hydrochloric acid and again with water, and finally dried, filtered and evaporated under reduced pressure. did. The residue was dissolved in anhydrous ethyl acetate and filtered through a silica gel column eluting with anhydrous ethyl acetate to obtain mono-2-(2-hydroxyethyl)ether.
(3-Benzoylphenyl)-propionate was isolated. After drying and evaporating the solvent, the product obtained was dissolved in benzene and the solution was treated with phosphorus pentachloride. After boiling the mixture for several hours, the reaction solvent was removed and the residue was fractionally distilled to form the 2-(3-benzoyl ether of hydroxyethyl-chloroethyl ether of formula (), where X = Cl). Enyl)-propionate was obtained. This halogen compound (3.61 g; 0.01 mol) was
-chlorobenzhydryl-piperazine (2.86 g;
0.01 mol; boiling point 178-180/0.5 mm) and the mixture was heated under stirring on a boiling water bath for 16 hours. After drying, an alkaline solution was added (PH8-9) and the mixture was extracted with dichloromethane. The organic solution was separated, dried and evaporated, and the residue was then treated with a saturated picric acid solution in ethanol, thus precipitating a partially elastic solid, which was crystallized several times from ethanol. A product with a melting point of 144-146 DEG C. (uncorrected) crystallized (yield 28%) having the same physico-chemical properties as those obtained in Example 3. Example 17 (Acute toxicity test) The results of the acute toxicity test on mice and rats of the compound of general formula () according to the present invention were as shown in Table 3 below.

【table】

[Table] Example 18 (Anti-inflammatory effect evaluation test) The anti-inflammatory effect of the compound of general formula () according to the present invention on carrageenan edema in rat paws was tested. Edema in male and female Sprague in our breeding area
Groups of Dawley rats (weighing 130-160 g) were challenged by a modification of Winter's method.
0.1 ml of a 2% carrageenan (lambda fraction) suspension in saline was injected into the thick part of the aponeurosis of the sole of the left foot of each rat. Test drugs were administered orally, usually 1 hour before carrageenan injection. The volume of the foot was measured using a blood volume meter (Basile, volume differential detection meter).
Measurements were taken at hourly intervals over a period of 4-5 hours.
The ED ₅₀ value, ie the dose that inhibits paw swelling by 50%, was calculated from data obtained 2, 3 and 4 hours after carrageenan injection. In one study to determine the duration of anti-edema effect,
Drugs were administered orally 2, 4, 6 and 12 hours before carrageenan injection. To determine the mechanism of anti-inflammatory action, male rats underwent bilateral adrenalectomy 4 days before the anti-edema test. The results obtained were as shown in Table 4.

【table】

[Table] The results in Table 4 clearly demonstrate the anti-inflammatory effect of the compounds of the present invention. Example 19 (Analgesic effect test) The analgesic effect test of the compound of general formula () according to the present invention on rat paw inflammation was tested by hypersensitivity. Male and female Sprague Dawley weighing 170-200g
A group of rats was used. Randall and Selitto
A modification of the method was used. Inflammation of the foot was injected
It was induced with 0.1 ml of a suspension of 10% Bruer's yeast or 2% carrageenan. The compounds to be tested were orally administered 2 hours after the injection of the inflammatory agent. Thirty and sixty minutes after injection of the test compound, paw pain sensitivity was measured using an analgesic measuring device (Basile). The results obtained are shown in Table 5.

[Table] The fifth result clearly shows the analgesic effect of the compound of the present invention.

Claims (1)

[Claims] 1 General formula () Compounds that are piperazine derivatives of and pharmaceutically acceptable organic and inorganic salts thereof. 2 General formula () In producing the piperazine derivative of formula () 2-(3-benzoylphenyl)-propionic acid or its derivatives with the formula () A method for producing the piperazine derivative, which comprises reacting it with piperazine alcohol or a derivative thereof. 3 The derivative of 2-(3-benzoylphenyl)-propionic acid has the formula () The method according to claim 2, which is a halide of (wherein, X is halogen). 4 The derivative of 2-(3-benzoylphenyl)-propionic acid has the formula () The method according to claim 2, which is a symmetric anhydride of. 5 The 2-(3-benzoylphenyl)-propionic acid derivative has the formula () (wherein R is alkyl, aryl or cycloalkyl), which is reacted with piperazine alcohol of formula () in an inert anhydrous organic solvent. . 6 2-(3-benzoylphenyl)- of formula ()
Approximately equimolar amounts of propionic acid and piperazine alcohol of the formula () are prepared by the formula () in an inert anhydrous organic solvent. The process according to claim 2, wherein the reaction is carried out in the presence of carbodiimides, each of which may be different, each being alkyl, aryl or cycloalkyl. 7 2-(3-benzoylphenyl)- of formula ()
3. The process according to claim 2, wherein approximately equimolar amounts of propionic acid and piperazine alcohol of formula () are reacted by using trifluoroacetic anhydride as an esterifying agent. 8 2-(3 of formula () dissolved in anhydrous pyridine
-Benzoylphenyl)-propionic acid is reacted with benzenesulfonyl halide, and then to the resulting mixture is added a piperazine alcohol of the formula () in an equimolar amount to the acid (). manufacturing method. 9. The production method according to claim 8, wherein p-toluenesulfonyl halide is used in place of benzenesulfonyl halide. 10 Equimolar amounts of 2-(3-benzoylphenyl)-propionic acid of formula () and piperazine alcohol of formula () are dissolved in an organic solvent and the inertness of 2-halogen-1-methyl-pyridinium iodide is 3. The method according to claim 2, which comprises adding the compound to a suspension in a solvent. 11. Process according to claim 10, using a suspension of 11 2-bromo-ethylpyridinium tetrafluoroborate in an inert solvent. 12 The salt of 2-(3-benzoylphenyl)-propionic acid of formula () is converted to the salt of formula () Process according to claim 2, characterized in that X is a halogen, preferably chlorine or bromine. 13 Formula () 2-(3-benzoylphenyl)-propionate of 2-halogen ethyleneoxyethyl-2'-ol with the formula (wherein X is halogen) The method according to claim 2, wherein the method is reacted with p-chlorobenzhydrylpiperazine.